1
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Zhou X, Liu W, Liang Z, Liang J, Zhang T, Gao W, Yang Z. Key epigenetic enzymes modulated by natural compounds contributes to tumorigenicity. Int J Biol Macromol 2025; 301:140391. [PMID: 39880237 DOI: 10.1016/j.ijbiomac.2025.140391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/21/2025] [Accepted: 01/26/2025] [Indexed: 01/31/2025]
Abstract
Dysregulation of epigenetic regulation is observed in numerous tumor cells. The therapeutic effects of natural products on tumors were investigated through a comprehensive analysis of active ingredients derived from various structured natural products. The analysis focuses on regulating key enzymes involved in epigenetic control. To study the modulation of these enzymes for tumor treatment, the structural characteristics of natural products that impact tumorigenesis were identified. The presence of specific patterns suggests that compounds sharing structural similarities can potentially induce therapeutic effects on identical tumors through modulation of distinct modifying enzymes. Structurally analogous natural products can likewise achieve therapeutic effects across diverse tumor types via their interaction with a common epigenetic enzyme. There exist numerous flavonoids with the capability to modulate METTL3, thereby influencing the development of various tumors. The normalization process was implemented to account for a common phenomenon, wherein structurally distinct compounds effectively target the same tumor by modulating a shared key enzyme. By summarizing, valuable insights into the role of compound-epigenetic enzymes in tumor development have been obtained. This discovery establishes a crucial scientific foundation for the prevention and treatment of tumor development through the utilization of structurally similar natural active ingredients.
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Affiliation(s)
- Xiaoyue Zhou
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wanqing Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ziqi Liang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiali Liang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wenyi Gao
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Zizhao Yang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of General Surgery, Shanghai Seventh People's Hospital, Shanghai 200137, China.
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2
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Yuan W, Lu G, Zhao Y, He X, Liao S, Wang Z, Lei X, Xie Z, Yang X, Tang S, Tang G, Deng X. Intranuclear TCA and mitochondrial overload: The nascent sprout of tumors metabolism. Cancer Lett 2025; 613:217527. [PMID: 39909232 DOI: 10.1016/j.canlet.2025.217527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/19/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
Abnormal glucose metabolism in tumors is a well-known form of metabolic reprogramming in tumor cells, the most representative of which, the Warburg effect, has been widely studied and discussed since its discovery. However, contradictions in a large number of studies and suboptimal efficacy of drugs targeting glycolysis have prompted us to further deepen our understanding of glucose metabolism in tumors. Here, we review recent studies on mitochondrial overload, nuclear localization of metabolizing enzymes, and intranuclear TCA (nTCA) in the context of the anomalies produced by inhibition of the Warburg effect. We provide plausible explanations for many of the contradictory points in the existing studies, including the causes of the Warburg effect. Furthermore, we provide a detailed prospective discussion of these studies in the context of these new findings, providing new ideas for the use of nTCA and mitochondrial overload in tumor therapy.
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Affiliation(s)
- Weixi Yuan
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Guozhong Lu
- 922nd Hospital of Hengyang, 421001, Hunan, China
| | - Yin Zhao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiang He
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Senyi Liao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhe Wang
- The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaoyong Lei
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Zhizhong Xie
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaoyan Yang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Shengsong Tang
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery Systems (2018TP1044), Hunan, 410007, China.
| | - Guotao Tang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Xiangping Deng
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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3
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Wang C, Liang W, Zhong J, Liu J, Zhou C, Ma C, Liao Y, Gao Y, Zhao J, He Y. m6A-mediated regulation of CPSF6 by METTL3 promotes oxaliplatin resistance in colorectal cancer through enhanced glycolysis. Cell Signal 2025; 130:111676. [PMID: 40010558 DOI: 10.1016/j.cellsig.2025.111676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/16/2024] [Accepted: 02/14/2025] [Indexed: 02/28/2025]
Abstract
Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) treatment. Recent studies have implicated CPSF6 in cancer progression and drug resistance, although its role in chemotherapy resistance and regulatory mechanisms is unclear. This study investigates CPSF6's involvement in oxaliplatin resistance in CRC and its regulation via m6A methylation by METTL3. We assessed CPSF6 expression in oxaliplatin-resistant (OxR) CRC cell lines (HT29-OxR and HCT116-OxR) compared to sensitive counterparts using qRT-PCR and Western blotting. CPSF6 was significantly upregulated in OxR cells, and its knockdown reduced cell viability, colony formation, and glycolytic activity while increasing apoptosis. m6A modification of CPSF6 mRNA was elevated in OxR cells, correlating with increased METTL3 expression. METTL3 knockdown decreased CPSF6 levels and m6A enrichment, enhancing mRNA degradation, while its overexpression stabilized CPSF6 mRNA, promoting resistance. Xenograft experiments showed that CPSF6 knockdown suppressed tumor growth and glycolysis. Thus, CPSF6 is identified as a mediator of oxaliplatin resistance in CRC, regulated by the METTL3/m6A axis, suggesting potential therapeutic targets to overcome resistance.
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Affiliation(s)
- Chengxing Wang
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Weijun Liang
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Jietao Zhong
- Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China; Department of Gastroenterology, Jiangmen Central Hospital, Guangdong 529000, China
| | - Jiachen Liu
- Department of Nuclear Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong 510000, China
| | - Chaorong Zhou
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Changyi Ma
- Department of Radiology, Jiangmen Central Hospital, Guangdong 529000, China
| | - Yuehua Liao
- Department of Pathology, Jiangmen Central Hospital, Guangdong 529000, China
| | - Yuan Gao
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Jinglin Zhao
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China.
| | - Yaoming He
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China.
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4
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Yu D, Zhong Q, Wang Y, Yin C, Bai M, Zhu J, Chen J, Li H, Hong W. Lactylation: The metabolic accomplice shaping cancer's response to radiotherapy and immunotherapy. Ageing Res Rev 2025; 104:102670. [PMID: 39864560 DOI: 10.1016/j.arr.2025.102670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/09/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
Protein lactylation, an emerging post-translational modification, is providing new insights into tumor biology and challenging our current understanding of cancer mechanisms. Our review illuminates the intricate roles of lactylation in carcinogenesis, tumor progression, and therapeutic responses, positioning it as a critical linchpin connecting metabolic reprogramming, epigenetic modulation, and treatment outcomes. We provide an in-depth analysis of lactylation's molecular mechanisms and its far-reaching impact on cell cycle regulation, immune evasion strategies, and therapeutic resistance within the complex tumor microenvironment. Notably, this review dissects the paradoxical nature of lactylation in cancer immunotherapy and radiotherapy. While heightened lactylation can foster immune suppression and radioresistance, strategically targeting lactylation cascades opens innovative avenues for amplifying the efficacy of current treatment paradigms. We critically evaluate lactylation's potential as a robust diagnostic and prognostic biomarker and explore frontier therapeutic approaches targeting lactylation. The synergistic integration of multi-omics data and artificial intelligence in lactylation research is catalyzing significant strides towards personalized cancer management. This review not only consolidates current knowledge but also charts a course for future investigations. Key research imperatives include deciphering tumor-specific lactylation signatures, optimizing synergistic strategies combining lactylation modulation with immune checkpoint inhibitors and radiotherapy, and comprehensively assessing the long-term physiological implications of lactylation intervention. As our understanding of lactylation's pivotal role in tumor biology continues to evolve, this burgeoning field promises to usher in transformative advancements in cancer diagnosis, treatment modalitie.
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Affiliation(s)
- Danqing Yu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Qingping Zhong
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Yanlin Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310000, China
| | - Chang Yin
- Nursing Department, Shanghai Sixth People's Hospital, Shanghai 200233, China
| | - Minghua Bai
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Ji Zhu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Jinggang Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| | - Huaming Li
- Department of Gastroenterology, Hangzhou Third Peoples Hospital, Hangzhou 310000, China.
| | - Weifeng Hong
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
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5
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Zeng Y, Jiang H, Chen Z, Xu J, Zhang X, Cai W, Zeng X, Ma P, Lin R, Yu H, He Y, Ying H, Zhou R, Wu X, Yu F. Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN. Cell Death Dis 2025; 16:59. [PMID: 39890782 PMCID: PMC11785747 DOI: 10.1038/s41419-025-07359-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 12/21/2024] [Accepted: 01/16/2025] [Indexed: 02/03/2025]
Abstract
FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. In this study, oxaliplatin (OXA)- and 5-fluorouracil (5-Fu)-resistant hepatocellular carcinoma cell lines were established, and enhanced glycolytic activity was identified in resistant cells. Inhibiting glycolysis effectively suppressed the malignant behavior of both OXA- and 5-Fu-resistant cells. Mechanistically, active glycolysis induced elevated levels of lactylation, predominantly histone lactylation, with H3K14la playing a key role in regulating gene expression. The ubiquitin E3 ligase NEDD4 was identified as a downstream target of H3K14la. Furthermore, NEDD4, regulated by histone lactylation, interacted with PTEN to mediate its ubiquitination and subsequent degradation. The downregulation of PTEN formed a positive feedback loop, further driving the malignant progression of OXA- and 5-Fu-resistant cells. This study elucidates a shared mechanism underlying OXA and 5-Fu resistance in hepatocellular carcinoma and highlights a promising therapeutic target for overcoming clinical chemotherapy resistance.
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MESH Headings
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- PTEN Phosphohydrolase/metabolism
- PTEN Phosphohydrolase/genetics
- Humans
- Liver Neoplasms/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Cell Line, Tumor
- Histones/metabolism
- Oxaliplatin/pharmacology
- Ubiquitination/drug effects
- Feedback, Physiological
- Nedd4 Ubiquitin Protein Ligases/metabolism
- Nedd4 Ubiquitin Protein Ligases/genetics
- Fluorouracil/pharmacology
- Fluorouracil/therapeutic use
- Animals
- Drug Resistance, Multiple/drug effects
- Mice, Nude
- Mice
- Gene Expression Regulation, Neoplastic/drug effects
- Glycolysis/drug effects
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Affiliation(s)
- Yuan Zeng
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haoran Jiang
- Department of Radiation Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhoufeng Chen
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jun Xu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangting Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weimin Cai
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xianjie Zeng
- School of Pharmaceutical Science, Fujian Medical University, Fujian, China
| | - Peipei Ma
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rong Lin
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huilin Yu
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuanhang He
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huiya Ying
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ruoru Zhou
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao Wu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Fujun Yu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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6
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Chen J, Ye M, Gu D, Yu P, Xu L, Xue B, Yan L, Lu F, Hu C, Xu Y, Shi X, Chen L, Wang Y, Bai J, Tian Y, Tang Q. FTO-induced APOE promotes the malignant progression of pancreatic neuroendocrine neoplasms through FASN-mediated lipid metabolism. Int J Biol Sci 2025; 21:1478-1496. [PMID: 39990672 PMCID: PMC11844274 DOI: 10.7150/ijbs.103428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/01/2025] [Indexed: 02/25/2025] Open
Abstract
N6-methyladenosine (m6A) is considered the most prevalent RNA epigenetic regulator in cancer. FTO, an m6A demethylase, has been implicated in contributing to the progression of various cancers by up-regulating the expression of multiple oncogenes. However, studies exploring its impact on lipid metabolism in cancer, especially in pNENs, remain scarce. In this study, we demonstrated that FTO was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, we discovered that FTO over-expression increased the expression of APOE in an m6A-IGF2BP2-dependent manner, leading to dysregulation of lipid metabolism. Furthermore, we found APOE could activate the PI3K/AKT/mTOR signaling pathway, thereby enhancing lipid metabolism and proliferative capabilities, by orchestrating the state of FASN ubiquitination. In conclusion, our study reveals the FTO/IGF2BP2/APOE/FASN/mTOR axis as a mechanism underlying aberrant m6A modification in lipid metabolism and provides new insights into the molecular basis for developing therapeutic strategies for pNENs treatment.
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Affiliation(s)
- Jinhao Chen
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
- Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Mujie Ye
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Danyang Gu
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Ping Yu
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Lin Xu
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Bingyang Xue
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Lijun Yan
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Feiyu Lu
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Chunhua Hu
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Yanling Xu
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Xiaoting Shi
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Lingyi Chen
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Yan Wang
- Digestive Endoscopy, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, China
- Department of Gastroenterology, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili State 835000, China
| | - Jianan Bai
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Ye Tian
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
| | - Qiyun Tang
- Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China
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7
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Li N, Wei X, Dai J, Yang J, Xiong S. METTL3: a multifunctional regulator in diseases. Mol Cell Biochem 2025:10.1007/s11010-025-05208-z. [PMID: 39853661 DOI: 10.1007/s11010-025-05208-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/04/2025] [Indexed: 01/26/2025]
Abstract
N6-methyladenosine (m6A) methylation is the most prevalent and abundant internal modification of mRNAs and is catalyzed by the methyltransferase complex. Methyltransferase-like 3 (METTL3), the best-known m6A methyltransferase, has been confirmed to function as a multifunctional regulator in the reversible epitranscriptome modulation of m6A modification according to follow-up studies. Accumulating evidence in recent years has shown that METTL3 can regulate a variety of functional genes, that aberrant expression of METTL3 is usually associated with many pathological conditions, and that its expression regulatory mechanism is related mainly to its methyltransferase activity or mRNA posttranslational modification. In this review, we discuss the regulatory functions of METTL3 in various diseases, including metabolic diseases, cardiovascular diseases, and cancer. We focus mainly on recent progress in identifying the downstream target genes of METTL3 and its underlying molecular mechanisms and regulators in the above systems. Studies have revealed that the use of METTL3 as a therapeutic target and a new diagnostic biomarker has broad prospects. We hope that this review can serve as a reference for further studies.
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Affiliation(s)
- Na Li
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang Wei
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jian Dai
- Department of Critical Care Medicine, Wuhan Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Jinfeng Yang
- Department of Medical Affairs, Wuhan Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China.
| | - Sizheng Xiong
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
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8
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Wu H, Chen S, Li X, Li Y, Shi H, Qing Y, Shi B, Tang Y, Yan Z, Hao Y, Wang D, Liu W. RNA modifications in cancer. MedComm (Beijing) 2025; 6:e70042. [PMID: 39802639 PMCID: PMC11718328 DOI: 10.1002/mco2.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 01/16/2025] Open
Abstract
RNA modifications are emerging as critical cancer regulators that influence tumorigenesis and progression. Key modifications, such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C), are implicated in various cellular processes. These modifications are regulated by proteins that write, erase, and read RNA and modulate RNA stability, splicing, translation, and degradation. Recent studies have highlighted their roles in metabolic reprogramming, signaling pathways, and cell cycle control, which are essential for tumor proliferation and survival. Despite these scientific advances, the precise mechanisms by which RNA modifications affect cancer remain inadequately understood. This review comprehensively examines the role RNA modifications play in cancer proliferation, metastasis, and programmed cell death, including apoptosis, autophagy, and ferroptosis. It explores their effects on epithelial-mesenchymal transition (EMT) and the immune microenvironment, particularly in cancer metastasis. Furthermore, RNA modifications' potential in cancer therapies, including conventional treatments, immunotherapy, and targeted therapies, is discussed. By addressing these aspects, this review aims to bridge current research gaps and underscore the therapeutic potential of targeting RNA modifications to improve cancer treatment strategies and patient outcomes.
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Affiliation(s)
- Han Wu
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Shi Chen
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Xiang Li
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Yuyang Li
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - He Shi
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Yiwen Qing
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Bohe Shi
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Yifei Tang
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Zhuoyi Yan
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Yang Hao
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Dongxu Wang
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Weiwei Liu
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
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9
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Wei S, Xia W, Feng J, Lu J, Zhang L, Wang W, Hu W, Geng Y. TRIM23 promotes 5-Fluorouracil resistance in colorectal cancer by upregulating GALNT4 expression. Apoptosis 2024:10.1007/s10495-024-02060-2. [PMID: 39720975 DOI: 10.1007/s10495-024-02060-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2024] [Indexed: 12/26/2024]
Abstract
5-Fluorouracil (5-FU) is one of the most common chemotherapeutic agents for colorectal cancer (CRC), but its application is often limited by resistance. Tripartite motif containing 23 (TRIM23) has been reported to be dysregulated in various tumors and involved in tumor progression and chemotherapy resistance. However, its relationship with CRC 5-FU resistance and the underlying mechanism are still unclear. In this study, we found that TRIM23 was upregulated in CRC. Patients treated with 5-FU and with high TRIM23 expression had a lower disease control rate (DCR) and a poorer median progression-free survival (mPFS). In vitro, the expression of TRIM23 in CRC cells was elevated after 5-FU treatment. Compared to parental cells, TRIM23 was significantly overexpressed in 5-FU-resistant CRC cells. Mechanistically, TRIM23 mediated 5-FU resistance of CRC by upregulating the expression of N-acetylgalactosaminyltransferase-4 (GALNT4). Knocking down TRIM23 in 5-FU-resistant colon cancer cells restored the sensitivity to 5-FU, while overexpression of GALNT4 in TRIM23 knockdown cells counteracted the chemosensitization caused by TRIM23 downregulation. The TRIM23/GALNT4 axis may play a crucial role in 5-FU resistance in CRC, and targeted inhibition of this axis is expected to reverse resistance. As a potential biomarker for screening 5-FU-sensitive patients and predicting prognosis in clinical practice, TRIM23 deserves further investigation.
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Affiliation(s)
- Shanshan Wei
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China
| | - Wei Xia
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China
| | - Jun Feng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China
| | - Jianwen Lu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China
| | - Luo Zhang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China
| | - Wei Wang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China.
| | - Yiting Geng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China.
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10
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Tang F, Xiao D, Li X, Qiao L. The roles of lactate and the interplay with m 6A modification in diseases. Cell Biol Toxicol 2024; 40:107. [PMID: 39617813 PMCID: PMC11609124 DOI: 10.1007/s10565-024-09951-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 11/20/2024] [Indexed: 12/13/2024]
Abstract
Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m6A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m6A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m6A modifications by enhancing the transcriptional expression levels of m6A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m6A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m6A alterations to impact lactate levels and subsequently affect lactylation processes.
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Affiliation(s)
- Fajuan Tang
- Department of Emergency, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China
| | - Dongqiong Xiao
- Department of Emergency, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China
| | - Xihong Li
- Department of Emergency, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China
| | - Lina Qiao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China.
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
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11
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Zhang Y, Shen Z, Han X, Wu Y, Huang T. Long non-coding RNA AC105118.1 affects glycolysis to facilitate oxaliplatin resistance in colorectal cancer cells by modulating the miR-378a-3p/KIF26B axis. Int J Biochem Cell Biol 2024; 177:106692. [PMID: 39536859 DOI: 10.1016/j.biocel.2024.106692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Oxaliplatin is a first-line chemotherapy drug for colorectal cancer (CRC), but many patients eventually lose treatment efficacy due to acquired resistance. AC105118.1 is a long non-coding RNA with unknown biological function. This research attempts to probe into the molecular regulatory mechanism of AC105118.1 in CRC oxaliplatin resistance. METHODS The expression level of AC105118.1 in CRC tissues and cells was measured based on The Cancer Genome Atlas (TCGA) data and quantitative reverse transcription polymerase chain reaction (qRT-PCR). We utilized dual-luciferase assay and RNA immunoprecipitation to analyze the interaction between AC105118.1, miR-378a-3p, and their downstream target KIF26B. CCK-8, colony formation assay, and flow cytometry were employed to assess the half inhibitory concentration (IC50), cell proliferation, and apoptosis rate of HCT116/L-OHP cells treated with oxaliplatin. The glycolysis evaluation was completed by measuring the extracellular acidification rate (ECAR), glucose consumption, lactate production, and glycolysis-related proteins (HK2, GLUT1, and LDHA). TUNEL staining was used to detect the level of apoptosis. RESULTS AC105118.1 was specifically upregulated in CRC tissues and cells. AC105118.1 indirectly facilitated the expression of miRNA target gene KIF26B by sequestering miR-378a-3p. In HCT116/L-OHP cells, transfection with si-AC105118.1 resulted in a decrease in glycolysis level, a lower maximum IC50 required for oxaliplatin-treated cells, inhibited cell proliferation, and an increase in apoptosis rate. All of these effects were alleviated when simultaneously transfecting miR-378a-3p inhibitor or oe-KIF26B. Knockdown of AC105118.1 significantly inhibited oxaliplatin resistance to CRC in mice. CONCLUSION AC105118.1 facilitates glycolysis and increases CRC cells' resistance to oxaliplatin by targeting the miR-378a-3p/KIF26B axis. The present work shed new insights into the function and mechanism of AC105118.1 in molecular function and suggested that the AC105118.1/miR-378a-3p/KIF26B axis is a promising target for intervening CRC oxaliplatin resistance.
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Affiliation(s)
- Yong Zhang
- Department of Surgery, AnYang Tumor Hospital, Anyang 455000, China
| | - Zhiling Shen
- Department of Surgery, AnYang Tumor Hospital, Anyang 455000, China
| | - Xiaodong Han
- Department of Surgery, AnYang Tumor Hospital, Anyang 455000, China
| | - Yachao Wu
- Department of Surgery, AnYang Tumor Hospital, Anyang 455000, China
| | - Tianchen Huang
- Department of Surgery, AnYang Tumor Hospital, Anyang 455000, China.
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12
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Lavudi K, Nuguri SM, Pandey P, Kokkanti RR, Wang QE. ALDH and cancer stem cells: Pathways, challenges, and future directions in targeted therapy. Life Sci 2024; 356:123033. [PMID: 39222837 DOI: 10.1016/j.lfs.2024.123033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/16/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024]
Abstract
Human ALDH comprise 19 subfamilies in which ALDH1A1, ALDH1A3, ALDH3A1, ALDH5A1, ALDH7A1, and ALDH18A1 are implicated in CSC. Studies have shown that ALDH can also be involved in drug resistance and standard chemotherapy regimens are ineffective in treating patients at the stage of disease recurrence. Existing chemotherapeutic drugs eliminate the bulk of tumors but are usually not effective against CSC which express ALDH+ population. Henceforth, targeting ALDH is convincing to treat the patient's post-relapse. Combination therapies that interlink signaling mechanisms seem promising to increase the overall disease-free survival rate. Therefore, targeting ALDH through ALDH inhibitors along with immunotherapies may create a novel platform for translational research. This review aims to fill in the gap between ALDH1 family members in relation to its cell signaling mechanisms, highlighting their potential as molecular targets to sensitize recurrent tumors and bring forward the future development concerning the current progress and draw backs. This review summarizes the role of cancer stem cells and their upregulation by maintaining the tumor microenvironment in which ALDH is specifically highlighted. It discusses the regulation of ALDH family proteins and the crosstalk between ALDH and CSC in relation to cancer metabolism. Furthermore, it establishes the correlation between ALDH involved signaling mechanisms and their specific targeted inhibitors, as well as their functional modularity, bioavailability, and mechanistic role in various cancers.
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Affiliation(s)
- Kousalya Lavudi
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
| | - Shreya Madhav Nuguri
- Department of Food science and Technology, The Ohio State University, Columbus, OH, United States
| | - Prashant Pandey
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, U.P., India; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | | | - Qi-En Wang
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States.
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13
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Jiang TQ, Wang H, Cheng WX, Xie C. Modulation of host N6-methyladenosine modification by gut microbiota in colorectal cancer. World J Gastroenterol 2024; 30:4175-4193. [PMID: 39493326 PMCID: PMC11525875 DOI: 10.3748/wjg.v30.i38.4175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/29/2024] [Accepted: 09/12/2024] [Indexed: 09/29/2024] Open
Abstract
As a research hotspot in the field of molecular biology, N6-methyladenosine (m6A) modification has made progress in the treatment of colorectal cancer (CRC), leukemia and other cancers. Numerous studies have demonstrated that the tumour microenvironment (TME) regulates the level of m6A modification in the host and activates a series of complex epigenetic signalling pathways through interactions with CRC cells, thus affecting the progression and prognosis of CRC. However, with the diversity in the composition of TME factors, this action is reciprocal and complex. Encouragingly, some studies have experimentally revealed that the intestinal flora can alter CRC cell proliferation by directly acting on m6A and thereby altering CRC cell proliferation. This review summarizes the data, supporting the idea that the intestinal flora can influence host m6A levels through pathways such as methyl donor metabolism and thus affect the progression of CRC. We also review the role of m6A modification in the diagnosis, treatment, and prognostic assessment of CRC and discuss the current status, limitations, and potential clinical value of m6A modification in this field. We propose that additional in-depth research on m6A alterations in CRC patients and their TME-related targeted therapeutic issues will lead to better therapeutic outcomes for CRC patients.
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Affiliation(s)
- Tian-Qi Jiang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
- The First Clinical Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hao Wang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
- The First Clinical Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Wang-XinJun Cheng
- Queen Mary College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Chuan Xie
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
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14
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Mondal P, Jayaprakash G, Meeran SM. The translational potential of epigenetic modulatory bioactive phytochemicals as adjuvant therapy against cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 390:140-185. [PMID: 39864894 DOI: 10.1016/bs.ircmb.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
In preclinical studies, bioactive phytochemicals have shown enormous potential therapeutic efficacy against various human malignancies. These natural compounds have been shown to possess an inherent potential to alter the molecular signaling pathways and epigenetic modulatory activity involved in multiple physiological functions. Recently, epigenetic therapy has emerged as an important therapeutic modality due to the reversible nature of epigenetic alterations. To date, epigenetic modulatory compounds, for example, DNA methyltransferase inhibitors 5-azacytidine and 5'-deoxyazacytidine, as well as histone deacetylase inhibitors Vorinostat, Romidepsin, and Belinostat (PXD101), have been clinically approved by the FDA for the treatment of patients of leukemia and myelodysplastic syndrome. However, these synthetic epigenetic inhibitors are not as effective against many of the solid tumors. Therefore, the epigenetic modulatory phytochemicals provide new hope for improving the treatment modality as neoadjuvant and adjuvant therapy. It has been established that targeting more than one protein in the transformed cells simultaneously, that is, the multi-targeted therapeutic approach, might invoke a better therapeutic response. Therefore, here, we are compiling diverse evidences of the translational potential of novel combinatorial approaches utilizing the epigenetic modulatory phytochemicals with available therapeutics in the course of cancer treatment.
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Affiliation(s)
- Priya Mondal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Gowthami Jayaprakash
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Syed Musthapa Meeran
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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15
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Zhang L, Mao Z, Yin K, Wang S. Review of METTL3 in colorectal cancer: From mechanisms to the therapeutic potential. Int J Biol Macromol 2024; 277:134212. [PMID: 39069066 DOI: 10.1016/j.ijbiomac.2024.134212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 07/10/2024] [Accepted: 07/25/2024] [Indexed: 07/30/2024]
Abstract
N6-methyladenosine (m6A), the most abundant modification in mRNAs, affects the fate of the modified RNAs at the post-transcriptional level and participants in various biological and pathological processes. Increasing evidence shows that m6A modification plays a role in the progression of many malignancies, including colorectal cancer (CRC). As the only catalytic subunit in methyltransferase complex, methyltransferase-like 3 (METTL3) is essential to the performance of m6A modification. It has been found that METTL3 is associated with the prognosis of CRC and significantly influences various aspects of CRC, such as cell proliferation, invasion, migration, metastasis, metabolism, tumor microcirculation, tumor microenvironment, and drug resistance. The relationship between METTL3 and gut-microbiota is also involved into the progression of CRC. Furthermore, METTL3 might be a viable target for CRC treatment to prolong survival. In this review, we comprehensively summarize the function of METTL3 in CRC and the underlying molecular mechanisms. We aim to deepen understanding and offer new ideas for diagnostic biomarkers and therapeutic targets for colorectal cancer.
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Affiliation(s)
- Lexuan Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China
| | - Zhenwei Mao
- Department of Laboratory Medicine, Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
| | - Kai Yin
- Department of General Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Shengjun Wang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China.
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16
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Zhang H, Sun F, Jiang S, Yang F, Dong X, Liu G, Wang M, Li Y, Su M, Wen Z, Yu C, Fan C, Li X, Zhang Z, Yang L, Li B. METTL protein family: focusing on the occurrence, progression and treatment of cancer. Biomark Res 2024; 12:105. [PMID: 39289775 PMCID: PMC11409517 DOI: 10.1186/s40364-024-00652-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/09/2024] [Indexed: 09/19/2024] Open
Abstract
Methyltransferase-like protein is a ubiquitous enzyme-like protein in the human body, with binding domains for nucleic acids, proteins and other small molecules, and plays an important role in a variety of biological behaviours in normal organisms and diseases, characterised by the presence of a methyltransferase-like structural domain and a structurally conserved SAM-binding domain formed by the seven-stranded β-fold structure in the center of the protein. With the deepening of research, the METTL protein family has been found to be abnormally expressed in a variety of tumor diseases, and the clarification of its relationship with tumor diseases can be used as a molecular therapeutic target and has an important role in the prognosis of tumors. In this paper, we review the structure, biological process, immunotherapy, drug-targeted therapy, and markers of the METTL protein family to provide new ideas for the diagnosis and treatment of tumors.
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Affiliation(s)
- Huhu Zhang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Fulin Sun
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
- Health Science Center, Qingdao University, Qingdao, 266071, China
| | - Shuyao Jiang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
- Health Science Center, Qingdao University, Qingdao, 266071, China
| | - Fanghao Yang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiaolei Dong
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Guoxiang Liu
- Department of Clinical Laboratory, Weifang People's Hospital, 151, Guangwen Streer, Weifang, 261041, China
| | - Mengjun Wang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Ya Li
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Mohan Su
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Ziyuan Wen
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Chunjuan Yu
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Chenkai Fan
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
- Health Science Center, Qingdao University, Qingdao, 266071, China
| | - Xiaoxia Li
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Zhe Zhang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Lina Yang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
| | - Bing Li
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
- Department of Dermatology, The Affiliated Haici Hospital of Qingdao University, Qingdao, 266003, China.
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17
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Chen D, Ji F, Zhou Q, Cheung H, Pan Y, Lau HCH, Liang C, Yang Z, Huang P, Wei Q, Cheung AHK, Kang W, Chen H, Yu J, Wong CC. RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m6A-Dependent Oncogenic Translation and Colorectal Tumorigenesis. Cancer Res 2024; 84:2856-2872. [PMID: 38900944 PMCID: PMC11372367 DOI: 10.1158/0008-5472.can-23-2081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 11/28/2023] [Accepted: 06/14/2024] [Indexed: 06/22/2024]
Abstract
The N6-methyladenosine (m6A) RNA-binding protein YTHDF1 is frequently overexpressed in colorectal cancer and drives chemotherapeutic resistance. To systematically identify druggable targets in colorectal cancer with high expression of YTHDF1, this study used a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets. RUVBL1/2 were overexpressed in primary colorectal cancer samples and represented independent predictors of poor patient prognosis. Functionally, loss of RUVBL1/2 preferentially impaired the growth of YTHDF1-high colorectal cancer cells, patient-derived primary colorectal cancer organoids, and subcutaneous xenografts. Mechanistically, YTHFD1 and RUVBL1/2 formed a positive feedforward circuit to accelerate oncogenic translation. YTHDF1 bound to m6A-modified RUVBL1/2 mRNA to promote translation initiation and protein expression. Coimmunoprecipitation and mass spectrometry identified that RUVBL1/2 reciprocally interacted with YTHDF1 at 40S translation initiation complexes. Consequently, RUVBL1/2 depletion stalled YTHDF1-driven oncogenic translation and nascent protein biosynthesis, leading to proliferative arrest and apoptosis. Ribosome sequencing revealed that RUVBL1/2 loss impaired the activation of MAPK, RAS, and PI3K-AKT signaling induced by YTHDF1. Finally, the blockade of RUVBL1/2 by the pharmacological inhibitor CB6644 or vesicle-like nanoparticle-encapsulated siRNAs preferentially arrested the growth of YTHDF1-expressing colorectal cancer in vitro and in vivo. Our findings show that RUVBL1/2 are potential prognostic markers and druggable targets that regulate protein translation in YTHDF1-high colorectal cancer. Significance: RUVBL1/2 inhibition is a therapeutic strategy to abrogate YTHDF1-driven oncogenic translation and overcome m6A dysregulation in colorectal cancer.
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Affiliation(s)
- Danyu Chen
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Fenfen Ji
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Qiming Zhou
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Henley Cheung
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Yasi Pan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Harry C.-H. Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Cong Liang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Zhenjie Yang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Pingmei Huang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Qinyao Wei
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Alvin H.-K. Cheung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Huarong Chen
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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18
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Wei X, Feng J, Chen L, Zhang C, Liu Y, Zhang Y, Xu Y, Zhang J, Wang J, Yang H, Han X, Wang G. METTL3-mediated m6A modification of LINC00520 confers glycolysis and chemoresistance in osteosarcoma via suppressing ubiquitination of ENO1. Cancer Lett 2024:217194. [PMID: 39168299 DOI: 10.1016/j.canlet.2024.217194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 06/20/2024] [Accepted: 08/16/2024] [Indexed: 08/23/2024]
Abstract
Chemoresistance remains the main obstacle limiting the treatment of osteosarcoma, seriously affecting the prognosis of adolescent patients with osteosarcoma. Recently, long non-coding RNAs (lncRNAs) were reported to be involved in chemoresistance, while the mechanisms of lncRNAs underlying osteosarcoma resistance to chemotherapy remain elusive. Here, LINC00520 was identified as a novel cisplatin resistance-related lncRNA in osteosarcoma, and its high expression was associated with poor prognosis of osteosarcoma patients. Functionally, LINC00520 could potentiate osteosarcoma resistance to cisplatin in vitro and in vivo. Mechanistically, LINC00520 bound to ENO1 and upregulated ENO1 protein expression by blocking FBXW7-mediated ENO1 ubiquitination and proteasomal degradation, thereby promoting glycolysis and ultimately inducing cisplatin resistance in osteosarcoma. Furthermore, METTL3 could stabilize and upregulate LINC00520 in an m6A-YTHDF2-dependent manner in osteosarcoma. This study proposes a novel lncRNA-driven mechanism for cisplatin resistance in osteosarcoma, and offers a promising therapeutic strategy for reversing chemoresistance in osteosarcoma by targeting the METTL3/LINC00520/ENO1/glycolysis axis.
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Affiliation(s)
- Xianfu Wei
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Jinyan Feng
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Long Chen
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Chao Zhang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Yongheng Liu
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Yan Zhang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Yao Xu
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Jin Zhang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Jinwu Wang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Houzhi Yang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Xiuxin Han
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
| | - Guowen Wang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
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Li F, Zeng C, Liu J, Wang L, Yuan X, Yuan L, Xia X, Huang W. The YTH domain-containing protein family: Emerging players in immunomodulation and tumour immunotherapy targets. Clin Transl Med 2024; 14:e1784. [PMID: 39135292 PMCID: PMC11319238 DOI: 10.1002/ctm2.1784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/12/2024] [Accepted: 07/16/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND The modification of N6-methyladenosine (m6A) plays a pivotal role in tumor by altering both innate and adaptive immune systems through various pathways, including the regulation of messenger RNA. The YTH domain protein family, acting as "readers" of m6A modifications, affects RNA splicing, stability, and immunogenicity, thereby playing essential roles in immune regulation and antitumor immunity. Despite their significance, the impact of the YTH domain protein family on tumor initiation and progression, as well as their involvement in tumor immune regulation and therapy, remains underexplored and lacks comprehensive review. CONCLUSION This review introduces the molecular characteristics of the YTH domain protein family and their physiological and pathological roles in biological behavior, emphasizing their mechanisms in regulating immune responses and antitumor immunity. Additionally, the review discusses the roles of the YTH domain protein family in immune-related diseases and tumor resistance, highlighting that abnormal expression or dysfunction of YTH proteins is closely linked to tumor resistance. KEY POINTS This review provides an in-depth understanding of the YTH domain protein family in immune regulation and antitumor immunity, suggesting new strategies and directions for immunotherapy of related diseases. These insights not only deepen our comprehension of m6A modifications and YTH protein functions but also pave the way for future research and clinical applications.
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Affiliation(s)
- Fenghe Li
- Department of Gynaecology and ObstetricsSecond Xiangya HospitalCentral South UniversityChangshaChina
| | - Chong Zeng
- Department of Respiratory and Critical Care MedicineThe Seventh Affiliated Hospital, Hengyang Medical School, University of South ChinaChangshaHunanChina
| | - Jie Liu
- Department of PathologyThe Affiliated Changsha Central Hospital, Hengyang Medical School, University of South ChinaChangshaHunanChina
| | - Lei Wang
- NHC Key Laboratory of Carcinogenesis and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of EducationCancer Research Institute, School of Basic Medical Science, Central South UniversityChangshaHunanChina
| | - Xiaorui Yuan
- Department of Gynaecology and ObstetricsSecond Xiangya HospitalCentral South UniversityChangshaChina
| | - Li Yuan
- Department of Nuclear MedicineThe Third Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Xiaomeng Xia
- Department of Gynaecology and ObstetricsSecond Xiangya HospitalCentral South UniversityChangshaChina
| | - Wei Huang
- Department of OncologyXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center of Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
- Research Center of Carcinogenesis and Targeted TherapyXiangya HospitalCentral South UniversityChangshaChina
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20
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Yu Y, Hai Y, Zhou H, Bao W, Hu X, Gao Y, Wu J. METTL3 Inhibition Suppresses Cell Growth and Survival in Colorectal Cancer via ASNS Downregulation. J Cancer 2024; 15:4853-4865. [PMID: 39132158 PMCID: PMC11310885 DOI: 10.7150/jca.96760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 06/29/2024] [Indexed: 08/13/2024] Open
Abstract
Background: Colorectal cancer (CRC) presents a significant global health burden, with high rates of incidence and mortality, and an urgent need to improve prognosis. STM2457, a novel small molecule inhibitor specific for N6-methyladenosine (m6A) catalytic enzyme Methyltransferase-like 3 (METTL3) has implicated significant treatment potentials in a few of types of cancer. However, its impact and underlying mechanism are still unclear in CRC cells. Methods: We used CCK-8 and colony formation assay to observe cell growth, flow cytometry and TUNEL approaches to detect cell apoptosis under the treatment of STM2457 on CRC cells in vitro or in vivo. RNA-sequencing, qRT-PCR and western blotting were performed to explore downstream effectors of STM2457. Messenger RNA stability was evaluated by qRT-PCR after treatment with actinomycin D. The methylated RNA immunoprecipitation (MeRIP) qPCR, dual-luciferase reporter analyses and m6A dot blotting were carried out to measure the m6A modification. Associated gene expression pattern and clinical relevance in CRC clinical tissue samples were analyzed using online database. Results: STM2457 exhibited a strong influence on cell growth suppression and apoptosis of CRC cells in vitro and subcutaneous xenograft growth in vivo. Asparagine synthetase (ASNS) was markedly downregulated upon STM2457 treatment or METTL3 knockdown and exogenous overexpression of ASNS could rescue the biological defects induced by STM2457. Mechanistically, the downregulation of ASNS by STM2457 may be due to the decrease of m6A modification level in ASNS mRNA mediated by METTL3. Conclusions: Our findings suggest that STM2457 may serve as a potential therapeutic agent and ASNS may be a new promising therapeutic target for CRC.
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Affiliation(s)
- Yang Yu
- Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Yanan Hai
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Hongfeng Zhou
- Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Wenfang Bao
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiaowei Hu
- Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Yong Gao
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jin Wu
- Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
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21
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An TY, Hu QM, Ni P, Hua YQ, Wang D, Duan GC, Chen SY, Jia B. N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway. World J Gastrointest Oncol 2024; 16:3270-3283. [PMID: 39072157 PMCID: PMC11271789 DOI: 10.4251/wjgo.v16.i7.3270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 05/09/2024] [Accepted: 05/20/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and is implicated in the development of gastric cancer (GC). The tumor microenvironment is characterized by hypoxia, where hypoxia-inducible factor-1α (HIF-1α) plays a key role as a transcription factor, but the mechanisms underlying H. pylori-induced HIF-1α expression and carcinogenesis remain unclear. AIM To explore the underlying mechanism of H. pylori-induced HIF-1α expression in promoting the malignant biological behavior of gastric epithelial cells (GES-1). METHODS The study was conducted with human GES-1 cells in vitro. Relative protein levels of methyltransferase-like protein 14 (METTL14), HIF-1α, main proteins of the PI3K/AKT pathway, epithelial-mesenchymal transition (EMT) biomarkers, and invasion indicators were detected by Western blot. Relative mRNA levels of METTL14 and HIF-1α were detected by quantitative reverse transcription-polymerase chain reaction. mRNA stability was evaluated using actinomycin D, and the interaction between METTL14 and HIF-1α was confirmed by immunofluorescence staining. Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay, respectively. RESULTS H. pylori promoted HIF-1α expression and activated the PI3K/AKT pathway. Notably, METTL14 was downregulated in H. pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1α expression. Functional experiments showed that the overexpression of HIF-1α or knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway, thereby driving a series of malignant transformation, such as EMT and cell proliferation, migration, and invasion. By contrast, the knockdown of HIF-1α or overexpression of METTL14 had an opposite effect. CONCLUSION H. pylori-induced underexpression of METTL14 promotes the translation of HIF-1α and accelerates tumor progression by activating the PI3K/AKT pathway. These results provide novel insights into the carcinogenesis of GC.
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Affiliation(s)
- Tong-Yan An
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Quan-Man Hu
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Peng Ni
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Yan-Qiao Hua
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Di Wang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Guang-Cai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Shuai-Yin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Bin Jia
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Chao X, Guo L, Ye C, Liu A, Wang X, Ye M, Fan Z, Luan K, Chen J, Zhang C, Liu M, Zhou B, Zhang X, Li Z, Luo Q. ALKBH5 regulates chicken adipogenesis by mediating LCAT mRNA stability depending on m 6A modification. BMC Genomics 2024; 25:634. [PMID: 38918701 PMCID: PMC11197345 DOI: 10.1186/s12864-024-10537-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 06/17/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. RESULTS The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. CONCLUSIONS In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.
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Affiliation(s)
- Xiaohuan Chao
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Lijin Guo
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Chutian Ye
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Aijun Liu
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xiaomeng Wang
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Mao Ye
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Zhexia Fan
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Kang Luan
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jiahao Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Chunlei Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Manqing Liu
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Bo Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Xiquan Zhang
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Zhenhui Li
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China.
- College of Animal Science, South China Agricultural University, Guangzhou, China.
| | - Qingbin Luo
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, China.
- College of Animal Science, South China Agricultural University, Guangzhou, China.
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23
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Huang Q, Liang Z, Huang Q, Li X, Xia J, Huang L, Huang LB, Ou C. Involvement of lncRNAs in the regulation of aerobic glycolysis in hepatocellular carcinoma: Main functions, regulatory mechanisms and potential therapeutic implications (Review). Oncol Rep 2024; 51:84. [PMID: 38666534 PMCID: PMC11082637 DOI: 10.3892/or.2024.8743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 04/11/2024] [Indexed: 05/04/2024] Open
Abstract
Even under aerobic conditions, tumor cells can reprogram their metabolism to preferentially metabolize glucose into lactic acid. This abnormal metabolic pattern, known as the 'Warburg' effect or aerobic glycolysis, promotes cancer progression. Long non‑coding RNAs (lncRNAs) are RNAs that are >200 nucleotides in length and do not have protein‑coding capabilities. However, these RNAs play a key role in tumor development. There is increasing evidence to indicate that lncRNAs regulate glucose metabolism in tumor cells by affecting metabolic enzymes and some signaling pathways, thereby regulating the occurrence and progression of hepatocellular carcinoma (HCC). Therefore, it is crucial to understand which lncRNAs play a regulatory role in HCC glycolysis and to determine the related molecular mechanisms. The present review summarized and discussed the functions of lncRNAs, focusing on the regulatory mechanisms of lncRNAs in the process of glycolysis in HCC. In addition, the present review suggests the importance of lncRNAs as future therapeutic targets for antitumor cell metabolism.
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Affiliation(s)
- Qiongqing Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
| | - Zhengui Liang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
| | - Qiqi Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
| | - Xueyu Li
- Experimental Research Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
| | - Jingjing Xia
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
| | - Lining Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
| | - Lin Bing Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
| | - Chao Ou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China
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24
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Li W, Wang Y, Li X, Wu H, Jia L. Dexmedetomidine hydrochloride plus sufentanil citrate inhibits glucose metabolism and epithelial‑mesenchymal transition in human esophageal squamous carcinoma KYSE30 cells by modulating the JAK/STAT3/HIF‑1α axis. Oncol Lett 2024; 27:273. [PMID: 38686357 PMCID: PMC11056934 DOI: 10.3892/ol.2024.14406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 11/10/2023] [Indexed: 05/02/2024] Open
Abstract
Dexmedetomidine hydrochloride (DEX-HCl) and sufentanil citrate (SFC) are commonly used anesthetic drugs for esophageal cancer (EC) surgery. The present study was performed to investigate the effect of DEX-HCl and SFC treatment on glucose metabolism and epithelial-mesenchymal transition in EC. Cell counting kit-8 (CCK8), clonogenic, wound healing and Transwell migration assays were performed to assess the effects of the DEX-HCl and SFC on KYSE30 cell proliferation, invasion and migration. Changes in lactate and glucose levels in KYSE30 cells were also detected. Western blot analysis was used to determine the protein expression levels of the JAK/STAT signaling pathway and glucose metabolism-related proteins. The results of CCK8, clonogenic and wound healing assays demonstrated that DEX-HCl and SFC inhibited KYSE30 cell proliferation, invasion and migration. Similarly, the combined DEX-HCl and SFC treatment significantly reduced lactate production, ATP production and glucose levels in KYSE30 cells. Western blotting indicated that DEX-HCl and SFC could reduce JAK/STAT and metastasis-related protein expression. Demonstrating a reduction in Hexokinase 2, matrix metallopeptidase 2 and 9, N-cadherin and lactate dehydrogenase A protein expression levels. The effects of DEX-HCl and SFC combined treatment were counteracted by the addition of JAK/STAT pathway activator RO8191, which suggested that DEX-HCl and SFC could serve a role in mediating the JAK/STAT signaling pathway in KYSE30 cells.
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Affiliation(s)
- Weijing Li
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yong Wang
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xiaolin Li
- Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Han Wu
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Li Jia
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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Liu S, Liu M, Li Y, Song Q. N6-methyladenosine-dependent signaling in colorectal cancer: Functions and clinical potential. Crit Rev Oncol Hematol 2024; 198:104360. [PMID: 38615872 DOI: 10.1016/j.critrevonc.2024.104360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/29/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the third most prevalent malignancy worldwide. Despite the gradual expansion of therapeutic options for CRC, its clinical management remains a formidable challenge. And, because of the current dearth of technical means for early CRC screening, most patients are diagnosed at an advanced stage. Therefore, it is imperative to develop novel diagnostic and therapeutic tools for this disease. N6-methyladenosine (m6A), the predominant RNA modification in eukaryotes, can be recognized by m6A-specific methylated reading proteins to modulate gene expression. Studies have revealed that CRC disrupts m6A homeostasis through various mechanisms, thereby sustaining aberrant signal transduction and promoting its own progression. Consequently, m6A-based diagnostic and therapeutic strategies have garnered widespread attention. Although utilizing m6A as a biomarker and drug target has demonstrated promising feasibility, existing observations primarily stem from preclinical models; henceforth necessitating further investigation and resolution of numerous outstanding issues.
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Affiliation(s)
- Shaojun Liu
- Department of Oncology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese medicine, Suzhou, Jiangsu, China
| | - Min Liu
- Department of Oncology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese medicine, Suzhou, Jiangsu, China
| | - Yuxuan Li
- Department of Oncology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese medicine, Suzhou, Jiangsu, China
| | - Qing Song
- Department of Oncology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese medicine, Suzhou, Jiangsu, China.
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26
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Geng Y, Zheng X, Zhang D, Wei S, Feng J, Wang W, Zhang L, Wu C, Hu W. CircHIF1A induces cetuximab resistance in colorectal cancer by promoting HIF1α-mediated glycometabolism alteration. Biol Direct 2024; 19:36. [PMID: 38715141 PMCID: PMC11075259 DOI: 10.1186/s13062-024-00478-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 04/29/2024] [Indexed: 05/12/2024] Open
Abstract
Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.
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Affiliation(s)
- Yiting Geng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Dachuan Zhang
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Shanshan Wei
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Jun Feng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Wei Wang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Luo Zhang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
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27
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Zhang Q, Luo Y, Qian B, Cao X, Xu C, Guo K, Wan R, Jiang Y, Wang T, Mei Z, Liu J, Lv C. A systematic pan-cancer analysis identifies LDHA as a novel predictor for immunological, prognostic, and immunotherapy resistance. Aging (Albany NY) 2024; 16:8000-8018. [PMID: 38709280 PMCID: PMC11132014 DOI: 10.18632/aging.205800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 03/18/2024] [Indexed: 05/07/2024]
Abstract
Lactate dehydrogenase A (LDHA), a critical enzyme involved in glycolysis, is broadly involved multiple biological functions in human cancers. It is reported that LDHA can impact tumor immune surveillance and induce the transformation of tumor-associated macrophages, highlighting its unnoticed function of LDHA in immune system. However, in human cancers, the role of LDHA in prognosis and immunotherapy hasn't been investigated. In this study, we analyzed the expression pattern and prognostic value of LDHA in pan-cancer and explored its association between tumor microenvironment (TME), immune infiltration subtype, stemness scores, tumor mutation burden (TMB), and immunotherapy resistance. We found that LDHA expression is tumor heterogeneous and that its high expression is associated with poor prognosis in multiple human cancers. In addition, LDHA expression was positively correlated with the presence of mononuclear/macrophage cells, and also promoted the infiltration of a range of immune cells. Genomic alteration of LDHA was common in different types of cancer, while with prognostic value in pan-cancers. Pan-cancer analysis revealed that the significant correlations existed between LDHA expression and tumor microenvironment (including stromal cells and immune cells) as well as stemness scores (DNAss and RNAss) across cancer types. Drug sensitivity analysis also revealed that LDHA was able to predict response to chemotherapy and immunotherapy. Furthermore, it was confirmed that knockdown of LDHA reduced proliferation and migration ability of lung cancer cells. Taken together, LDHA could serve as a prognostic biomarker and a potential immunotherapy marker.
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Affiliation(s)
- Qiqi Zhang
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, P.R. China
- Southwest Medical University, Luzhou, P.R. China
| | - Yuanning Luo
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, P.R. China
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, P.R. China
| | - Bingshuo Qian
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, P.R. China
- School of Pharmacy, Henan University, Kaifeng, P.R. China
| | - Xiuhua Cao
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, P.R. China
| | - Caijun Xu
- Southwest Medical University, Luzhou, P.R. China
| | - Kan Guo
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, P.R. China
- Southwest Medical University, Luzhou, P.R. China
| | - Runlan Wan
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, P.R. China
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, P.R. China
| | - Yaling Jiang
- Southwest Medical University, Luzhou, P.R. China
| | - Tiecheng Wang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, P.R. China
| | - Zhiqiang Mei
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, P.R. China
- Southwest Medical University, Luzhou, P.R. China
| | - Jinbiao Liu
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, P.R. China
| | - Chaoxiang Lv
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, P.R. China
- Southwest Medical University, Luzhou, P.R. China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, P.R. China
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28
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Li G, Yao Q, Liu P, Zhang H, Liu Y, Li S, Shi Y, Li Z, Zhu W. Critical roles and clinical perspectives of RNA methylation in cancer. MedComm (Beijing) 2024; 5:e559. [PMID: 38721006 PMCID: PMC11077291 DOI: 10.1002/mco2.559] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 04/02/2024] [Accepted: 04/11/2024] [Indexed: 01/06/2025] Open
Abstract
RNA modification, especially RNA methylation, is a critical posttranscriptional process influencing cellular functions and disease progression, accounting for over 60% of all RNA modifications. It plays a significant role in RNA metabolism, affecting RNA processing, stability, and translation, thereby modulating gene expression and cell functions essential for proliferation, survival, and metastasis. Increasing studies have revealed the disruption in RNA metabolism mediated by RNA methylation has been implicated in various aspects of cancer progression, particularly in metabolic reprogramming and immunity. This disruption of RNA methylation has profound implications for tumor growth, metastasis, and therapy response. Herein, we elucidate the fundamental characteristics of RNA methylation and their impact on RNA metabolism and gene expression. We highlight the intricate relationship between RNA methylation, cancer metabolic reprogramming, and immunity, using the well-characterized phenomenon of cancer metabolic reprogramming as a framework to discuss RNA methylation's specific roles and mechanisms in cancer progression. Furthermore, we explore the potential of targeting RNA methylation regulators as a novel approach for cancer therapy. By underscoring the complex mechanisms by which RNA methylation contributes to cancer progression, this review provides a foundation for developing new prognostic markers and therapeutic strategies aimed at modulating RNA methylation in cancer treatment.
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Affiliation(s)
- Ganglei Li
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Qinfan Yao
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Peixi Liu
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Hongfei Zhang
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Yingjun Liu
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Sichen Li
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Yuan Shi
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Zongze Li
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Wei Zhu
- Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
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29
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Zhao L, Guo J, Xu S, Duan M, Liu B, Zhao H, Wang Y, Liu H, Yang Z, Yuan H, Jiang X, Jiang X. Abnormal changes in metabolites caused by m 6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application. J Adv Res 2024:S2090-1232(24)00159-0. [PMID: 38677545 DOI: 10.1016/j.jare.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 04/14/2024] [Accepted: 04/14/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor. AIM OF REVIEW The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations. KEY SCIENTIFIC CONCEPTS OF REVIEW This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.
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Affiliation(s)
- Liang Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; Department of Colorectal Anal Surgery, Shenyang Coloproctology Hospital, Shenyang 110002, China.
| | - Junchen Guo
- Department of Radiology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Shasha Xu
- Department of Gastroendoscopy, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Meiqi Duan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Baiming Liu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - He Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Yihan Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Haiyang Liu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Hexue Yuan
- Department of Colorectal Anal Surgery, Shenyang Coloproctology Hospital, Shenyang 110002, China.
| | - Xiaodi Jiang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang 110020, China.
| | - Xiaofeng Jiang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
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30
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Liu WW, Zheng SQ, Li T, Fei YF, Wang C, Zhang S, Wang F, Jiang GM, Wang H. RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy. Signal Transduct Target Ther 2024; 9:70. [PMID: 38531882 DOI: 10.1038/s41392-024-01777-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/08/2024] [Accepted: 02/19/2024] [Indexed: 03/28/2024] Open
Abstract
Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.
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Affiliation(s)
- Wei-Wei Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- School of Clinical Medicine, Shandong University, Jinan, China
| | - Si-Qing Zheng
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Tian Li
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Yun-Fei Fei
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Chen Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Shuang Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Fei Wang
- Neurosurgical Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
| | - Guan-Min Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
| | - Hao Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China.
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31
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Miao L, Lu C, Zhang B, Li H, Zhao X, Chen H, Liu Y, Cui X. Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy. J Transl Med 2024; 22:229. [PMID: 38433193 PMCID: PMC10909296 DOI: 10.1186/s12967-024-05033-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 02/24/2024] [Indexed: 03/05/2024] Open
Abstract
Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.
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Affiliation(s)
- Linxuan Miao
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116000, People's Republic of China
| | - Chenglin Lu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Bin Zhang
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Huili Li
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116000, People's Republic of China
| | - Xu Zhao
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116000, People's Republic of China
| | - Haoran Chen
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116000, People's Republic of China
| | - Ying Liu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China.
- Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, People's Republic of China.
| | - Xiaonan Cui
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China.
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32
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Jia X, He X, Huang C, Li J, Dong Z, Liu K. Protein translation: biological processes and therapeutic strategies for human diseases. Signal Transduct Target Ther 2024; 9:44. [PMID: 38388452 PMCID: PMC10884018 DOI: 10.1038/s41392-024-01749-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 01/13/2024] [Accepted: 01/18/2024] [Indexed: 02/24/2024] Open
Abstract
Protein translation is a tightly regulated cellular process that is essential for gene expression and protein synthesis. The deregulation of this process is increasingly recognized as a critical factor in the pathogenesis of various human diseases. In this review, we discuss how deregulated translation can lead to aberrant protein synthesis, altered cellular functions, and disease progression. We explore the key mechanisms contributing to the deregulation of protein translation, including functional alterations in translation factors, tRNA, mRNA, and ribosome function. Deregulated translation leads to abnormal protein expression, disrupted cellular signaling, and perturbed cellular functions- all of which contribute to disease pathogenesis. The development of ribosome profiling techniques along with mass spectrometry-based proteomics, mRNA sequencing and single-cell approaches have opened new avenues for detecting diseases related to translation errors. Importantly, we highlight recent advances in therapies targeting translation-related disorders and their potential applications in neurodegenerative diseases, cancer, infectious diseases, and cardiovascular diseases. Moreover, the growing interest lies in targeted therapies aimed at restoring precise control over translation in diseased cells is discussed. In conclusion, this comprehensive review underscores the critical role of protein translation in disease and its potential as a therapeutic target. Advancements in understanding the molecular mechanisms of protein translation deregulation, coupled with the development of targeted therapies, offer promising avenues for improving disease outcomes in various human diseases. Additionally, it will unlock doors to the possibility of precision medicine by offering personalized therapies and a deeper understanding of the molecular underpinnings of diseases in the future.
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Affiliation(s)
- Xuechao Jia
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China
| | - Xinyu He
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China
| | - Chuntian Huang
- Department of Pathology and Pathophysiology, Henan University of Chinese Medicine, Zhengzhou, Henan, 450000, China
| | - Jian Li
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, Henan, 450052, China.
- Research Center for Basic Medicine Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, 450000, China.
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, Henan, 450052, China.
- Research Center for Basic Medicine Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, 450000, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan, 450000, China.
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450000, China.
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Shao C, Han Y, Huang Y, Zhang Z, Gong T, Zhang Y, Tian X, Fang M, Han X, Li M. Targeting key RNA methylation enzymes to improve the outcome of colorectal cancer chemotherapy (Review). Int J Oncol 2024; 64:17. [PMID: 38131226 PMCID: PMC10783943 DOI: 10.3892/ijo.2023.5605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
RNA methylation modifications are closely linked to tumor development, migration, invasion and responses to various therapies. Recent studies have shown notable advancements regarding the roles of RNA methylation in tumor immunotherapy, the tumor microenvironment and metabolic reprogramming. However, research on the association between tumor chemoresistance and N6‑methyladenosine (m6A) methyltransferases in specific cancer types is still scarce. Colorectal cancer (CRC) is among the most common gastrointestinal cancers worldwide. Conventional chemotherapy remains the predominant treatment modality for CRC and chemotherapy resistance is the primary cause of treatment failure. The expression levels of m6A methyltransferases, including methyltransferase‑like 3 (METTL3), METTL14 and METTL16, in CRC tissue samples are associated with patients' clinical outcomes and chemotherapy efficacy. Natural pharmaceutical ingredients, such as quercetin, have the potential to act as METTL3 inhibitors to combat chemotherapy resistance in patients with CRC. The present review discussed the various roles of different types of key RNA methylation enzymes in the development of CRC, focusing on the mechanisms associated with chemotherapy resistance. The progress in the development of certain inhibitors is also listed. The potential of using natural remedies to develop antitumor medications that target m6A methylation is also outlined.
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Affiliation(s)
- Chiyun Shao
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
- No. 3 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yanjie Han
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
- No. 3 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yuying Huang
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
- No. 3 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Zhe Zhang
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
- No. 3 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Tao Gong
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
| | - Yajie Zhang
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
- Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
| | - Xiaokang Tian
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
| | - Mingzhi Fang
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
| | - Xuan Han
- School of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Min Li
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
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34
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Yu L, Gao Y, Bao Q, Xu M, Lu J, Du W. Effects of N6-methyladenosine modification on metabolic reprogramming in digestive tract tumors. Heliyon 2024; 10:e24414. [PMID: 38293446 PMCID: PMC10826742 DOI: 10.1016/j.heliyon.2024.e24414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 02/01/2024] Open
Abstract
N6-methyladenosine (m6A), the most abundant RNA modification within cells, participates in various biological and pathological processes, including self-renewal, invasion and proliferation, drug resistance, and stem cell characteristics. The m6A methylation plays a crucial role in tumors by regulating multiple RNA processes such as transcription, processing, and translation. Three protein types are primarily involved in m6A methylation: methyltransferases (such as METTL3, METTL14, ZC3H13, and KIAA1429), demethylases (such as FTO, ALKBH5), and RNA-binding proteins (such as the family of YTHDF, YTHDC1, YTHDC2, and IGF2BPs). Various metabolic pathways are reprogrammed in digestive tumors to meet the heightened growth demands and sustain cellular functionality. Recent studies have highlighted the extensive impact of m6A on the regulation of digestive tract tumor metabolism, further modulating tumor initiation and progression. Our review aims to provide a comprehensive understanding of the expression patterns, functional roles, and regulatory mechanisms of m6A in digestive tract tumor metabolism-related molecules and pathways. The characterization of expression profiles of m6A regulatory factors and in-depth studies on m6A methylation in digestive system tumors may provide new directions for clinical prediction and innovative therapeutic interventions.
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Affiliation(s)
- Liang Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yuan Gao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qiongling Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Min Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Weibo Du
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
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Wang G, Zheng H, Xiang Y, Wang Y, Wang K, Ren X, Du J. Identifying the critical oncogenic mechanism of LDHA based on a prognostic model of T-cell synthetic drivers. Int Immunopharmacol 2024; 126:111265. [PMID: 38000233 DOI: 10.1016/j.intimp.2023.111265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023]
Abstract
BACKGROUND Despite its early success, immunotherapy focused on removing T-cell inhibition does not achieve the desired effect in most patients. New strategies that target antigen-driven T-cell activation are needed to improve immunotherapy outcomes. However, a comprehensive analysis of synthetic drivers of T-cells is greatly lacking in lung adenocarcinoma (LUAD) and other types of tumors. METHODS We comprehensively evaluated the patterns of LUAD patients based on T -cell synthetic drivers by unsupervised clustering analysis. A risk model was constructed using Lasso Cox regression analysis. The predicted survival and immunotherapy efficacy of the model was validated by independent cohorts. Finally, single-cell sequencing analysis, and a series of in vitro experiments were conducted to explore the role of lactate dehydrogenase A (LDHA) in the malignant progression of LUAD. RESULTS Patients in the high-risk group were characterized by survival disadvantage, a "cold" immune phenotype, and by not having benefitted from immunotherapy. LDHA was shown to promote LUAD cell proliferation, cell cycle, invasion, and migration. Secondly, we found that LDHA induced NF-κB pathway activation, tyrosine kinase inhibitor resistance and immunosuppressant microenvironment. Finally, LDHA was found to be highly expressed in fibroblasts, which may be involved in promoting TKI resistance and mediating the immune escape. CONCLUSION This study revealed that the T-cell synthetic driver-associated prognostic model developed herein significantly predicted prognosis and immunotherapy efficacy in LUAD. We further investigated the role of LDHA in the malignant phenotype of tumor cells and tumor microenvironment remodeling, providing a promising and novel therapeutic strategy for LUAD.
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Affiliation(s)
- Guanghui Wang
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China; Department of Thoracic Surgery, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, China
| | - Haotian Zheng
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Yunzhi Xiang
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Yadong Wang
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Kai Wang
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China; Department of Healthcare Respiratory Medicine, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Xiaoyang Ren
- Department of Thoracic Surgery, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, China
| | - Jiajun Du
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China; Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China.
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Gu J, Cao H, Chen X, Zhang XD, Thorne RF, Liu X. RNA m6A modifications regulate crosstalk between tumor metabolism and immunity. WILEY INTERDISCIPLINARY REVIEWS. RNA 2024; 15:e1829. [PMID: 38114887 DOI: 10.1002/wrna.1829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 11/20/2023] [Accepted: 11/27/2023] [Indexed: 12/21/2023]
Abstract
In recent years, m6A modifications in RNA transcripts have arisen as a hot topic in cancer research. Indeed, a number of independent studies have elaborated that the m6A modification impacts the behavior of tumor cells and tumor-infiltrating immune cells, altering tumor cell metabolism along with the differentiation and functional activity of immune cells. This review elaborates on the links between RNA m6A modifications, tumor cell metabolism, and immune cell behavior, discussing this topic from the viewpoint of reciprocal regulation through "RNA m6A-tumor cell metabolism-immune cell behavior" and "RNA m6A-immune cell behavior-tumor cell metabolism" axes. In addition, we discuss the various factors affecting RNA m6A modifications in the tumor microenvironment, particularly the effects of hypoxia associated with cancer cell metabolism along with immune cell-secreted cytokines. Our analysis proposes the conclusion that RNA m6A modifications support widespread interactions between tumor metabolism and tumor immunity. With the current viewpoint that long-term cancer control must tackle cancer cell malignant behavior while strengthening anti-tumor immunity, the recognition of RNA m6A modifications as a key factor provides a new direction for the targeted therapy of tumors. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Affiliation(s)
- Jinghua Gu
- School of Life Sciences, Anhui Medical University, Hefei, China
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Huake Cao
- School of Life Sciences, Anhui Medical University, Hefei, China
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Xiaoli Chen
- Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial Key Laboratory of Long Non-coding RNA and Cancer Metabolism, Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan, China
| | - Xu Dong Zhang
- Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial Key Laboratory of Long Non-coding RNA and Cancer Metabolism, Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan, China
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia
| | - Rick F Thorne
- Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial Key Laboratory of Long Non-coding RNA and Cancer Metabolism, Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan, China
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia
| | - Xiaoying Liu
- School of Life Sciences, Anhui Medical University, Hefei, China
- Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial Key Laboratory of Long Non-coding RNA and Cancer Metabolism, Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan, China
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Rong H, Wang D, Wang Y, Dong C, Wang G. YTHDF1 in Tumor Cell Metabolism: An Updated Review. Molecules 2023; 29:140. [PMID: 38202722 PMCID: PMC10779796 DOI: 10.3390/molecules29010140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
With the advancement of research on m6A-related mechanisms in recent years, the YTHDF protein family within m6A readers has garnered significant attention. Among them, YTHDF1 serves as a pivotal member, playing a crucial role in protein translation, tumor proliferation, metabolic reprogramming of various tumor cells, and immune evasion. In addition, YTHDF1 also exerts regulatory effects on tumors through multiple signaling pathways, and numerous studies have confirmed its ability to assist in the reprogramming of the tumor cell-related metabolic processes. The focus of research on YTHDF1 has shifted in recent years from its m6A-recognition and -modification function to the molecular mechanisms by which it regulates tumor progression, particularly by exploring the regulatory factors that interact with YTHDF1 upstream and downstream. In this review, we elucidate the latest signaling pathway mechanisms of YTHDF1 in various tumor cells, with a special emphasis on its distinctive characteristics in tumor cell metabolic reprogramming. Furthermore, we summarize the latest pathological and physiological processes involving YTHDF1 in tumor cells, and analyze potential therapeutic approaches that utilize YTHDF1. We believe that YTHDF1 represents a highly promising target for future tumor treatments and a novel tumor biomarker.
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Affiliation(s)
| | | | | | | | - Guiling Wang
- Key Laboratory of Cell Biology, Department of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China; (H.R.); (D.W.); (Y.W.); (C.D.)
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Jing L, Zhou K, Wang Z, Li Y, Fan Y, Liu T, Shan Z, Lin Y. YTHDF1 shapes "cold" tumor and inhibits CD8 + T cells infiltration and function in breast cancer. Exp Cell Res 2023; 432:113778. [PMID: 37741489 DOI: 10.1016/j.yexcr.2023.113778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/25/2023]
Abstract
While YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) was recognized as a crucial contributor in the development and immune-related regulation of various types of tumors, its function in the immune response of breast cancer has largely remained uninvestigated. Through analysis of public databases, we found YTHDF1 as a highly expressed gene in breast cancers and confirmed this finding in breast cancer cells and clinical specimens from our center. Subsequently, we examined the link between YTHDF1 expression and immune cells and molecules by utilizing immune-related public databases and algorithm. We further validated our findings through cellular and animal experiments, as well as RNA sequencing. YTHDF1 was found highly expressed in tumor tissues of breast cancer, which negatively correlated with patient survival. The downregulation of YTHDF1 promoted the expression of pro-inflammatory markers and improved the anti-cancer ability of immune cells in breast cancer. RNA sequencing analysis revealed that YTHDF1 knockdown resulted in enrichment of differential genes in signal transduction pathways. Additionally, in vitro experiments showed that immune cells had higher cytotoxicity against breast cancer cells with decreased YTHDF1 expression. Moreover, in vivo studies indicated that YTHDF1 promoted breast cancer growth while inhibiting CD8+ T cell infiltration and function. Our study demonstrates that YTHDF1 plays a crucial role in establishing a "cold" tumor microenvironment in breast cancer by inhibiting the release of pro-inflammatory cytokines from cancer cells. As a result, the infiltration and functional differentiation of anti-tumor CD8+ T cells are hindered, ultimately resulting in the immune evasion of breast cancer.
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Affiliation(s)
- Lanyu Jing
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
| | - Kaiwen Zhou
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
| | - Zilin Wang
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
| | - Yuying Li
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
| | - Yuanjian Fan
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
| | - Ting Liu
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
| | - Zhen Shan
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
| | - Ying Lin
- Department of Breast Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
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Mao Z, Wang B, Zhang T, Cui B. The roles of m6A methylation in cervical cancer: functions, molecular mechanisms, and clinical applications. Cell Death Dis 2023; 14:734. [PMID: 37951987 PMCID: PMC10640579 DOI: 10.1038/s41419-023-06265-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 11/14/2023]
Abstract
Cervical cancer (CC) is a gynecological neoplasm with the highest incidence rate, primarily attributed to the persistent infection of high-risk Human papillomavirus (HPV). Despite extensive research, the pathogenesis of CC remains unclear. N6-methyladenosine (m6A) methylation, the most prevalent form of epigenetic modification in RNA, is intricately linked to cell proliferation, metastasis, metabolism, and therapeutic resistance within the tumor microenvironment (TME) of CC. The involvement of the writer, reader, and eraser in m6A modification impacts the advancement of tumors through the regulation of RNA stability, nuclear export, translation efficiency, and RNA degradation. Here, we discuss the biogenesis of m6A, the atypical expressions of m6A regulators, the mechanisms of molecular interactions, and their functions in CC. Furthermore, we elucidate m6A modification of non-coding RNA. In the context of precision medicine, and with the advancements of genomics, proteomics, and high-throughput sequencing technologies, we summarize the application of m6A in the clinical diagnosis and treatment of CC. Additionally, new perspectives on detection methods, immune regulation, and nano-drug development are presented, which lay the foundation for further research of m6A and provide new ideas for the clinical treatment of CC.
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Affiliation(s)
- Zhonghao Mao
- Cheeloo College of Medicine, Shandong University, No. 44 Wenhua West Road, Jinan City, 250012, Shandong Province, China
| | - Bingyu Wang
- Cheeloo College of Medicine, Shandong University, No. 44 Wenhua West Road, Jinan City, 250012, Shandong Province, China
| | - Teng Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan City, 250012, Shandong Province, China
| | - Baoxia Cui
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan City, 250012, Shandong Province, China.
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Yao J, Song Y, Yu X, Lin Z. Interaction between N 6-methyladenosine modification and the tumor microenvironment in colorectal cancer. Mol Med 2023; 29:129. [PMID: 37737134 PMCID: PMC10515252 DOI: 10.1186/s10020-023-00726-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 09/08/2023] [Indexed: 09/23/2023] Open
Abstract
The incidence and mortality of colorectal cancer (CRC) are rapidly increasing worldwide. Recently, there has been significant attention given to N6-methyladenosine (m6A), the most common mRNA modification, especially for its effects on CRC development. It is important to note that the progression of CRC would be greatly hindered without the tumor microenvironment (TME). The interaction between CRC cells and their surroundings can activate and influence complex signaling mechanisms of epigenetic changes to affect the survival of tumor cells with a malignant phenotype. Additionally, the TME is influenced by m6A regulatory factors, impacting the progression and prognosis of CRC. In this review, we describe the interactions and specific mechanisms between m6A modification and the metabolic, hypoxia, inflammatory, and immune microenvironments of CRC. Furthermore, we summarize the therapeutic role that m6A modification can play in the CRC microenvironment, and discuss the current status, limitations, and potential future directions in this field. This review aims to provide new insights into the molecular targets and theoretical foundations for the treatment of CRC.
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Affiliation(s)
- Jiali Yao
- Department of Immunology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yeke Song
- Department of Immunology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Xiaoping Yu
- Health Management Center, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Zhijie Lin
- Department of Immunology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China.
- Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, 225001, China.
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Pang Y, Chen X, Xu B, Zhang Y, Liang S, Hu J, Liu R, Luo X, Wang Y. Engineered multitargeting exosomes carrying miR-323a-3p for CRC therapy. Int J Biol Macromol 2023; 247:125794. [PMID: 37442504 DOI: 10.1016/j.ijbiomac.2023.125794] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/03/2023] [Accepted: 07/09/2023] [Indexed: 07/15/2023]
Abstract
Colorectal cancer (CRC) is in the forefront of malignancies for its high incidence and mortality. 5-Fluorouracil (5-FU) is one of the most widely used effective drugs for the treatment of CRC. However, there is an urgent need in reducing its systemic side effects and chemoresistance, in order to make 5-FU-based chemotherapy more effective in the treatment of CRC. In this study, engineered CRC cells were established to overexpress miR-323a-3p, which was a tumor suppressor that targeted both EGFR and TYMS. Then miR-323a-3p-loaded exosomes (miR-Exo) were obtained with suitable methods of collection and purification. We found that miR-Exo significantly inhibited CRC cell proliferation and induced apoptosis by the way of targeting EGFR directly in the cells, which eventually led to desirable tumor regression in the cell derived xenograft (CDX) and patient derived xenograft (PDX) tumor mice models. Moreover, we discovered that miR-323a-3p released from miR-Exo directly inhibited the upregulation of thymidylate synthase (TYMS) induced by 5-FU-resistence in CRC cells, resulting in the revival of tumor cytotoxicity from 5-FU. MiR-Exo could effectively induce the CRC cell apoptosis by targeting EGFR and TYMS, and enhance the therapeutic effects of 5-FU on CRC. Our work demonstrates the potency of miR-Exo for advanced CRC biotherapy.
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Affiliation(s)
- Yechun Pang
- Department of General Surgery, Pudong New Area People's Hospital, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingshi Chen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baiying Xu
- Department of General Surgery, Pudong New Area People's Hospital, China
| | - Yuanzhou Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shunshun Liang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingying Hu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xiaoying Luo
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Yunfeng Wang
- Department of General Surgery, Pudong New Area People's Hospital, China.
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Yue SW, Liu HL, Su HF, Luo C, Liang HF, Zhang BX, Zhang W. m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism. Mol Cancer 2023; 22:137. [PMID: 37582735 PMCID: PMC10426175 DOI: 10.1186/s12943-023-01841-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/05/2023] [Indexed: 08/17/2023] Open
Abstract
Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cancer. The n6-methyladenosine (m6A) modification of RNA is widespread in eukaryotic cells. Dynamic and reversible m6A modifications are widely involved in the regulation of cancer stem cell renewal and differentiation, tumor therapy resistance, tumor microenvironment, tumor immune escape, and tumor metabolism. Lately, more and more evidences show that m6A modification can affect the glycolysis process of tumors in a variety of ways to regulate the biological behavior of tumors. In this review, we discussed the role of glycolysis in tumor genesis and development, and elaborated in detail the profound impact of m6A modification on different tumor by regulating glycolysis. We believe that m6A modified glycolysis has great significance and potential for tumor treatment.
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Affiliation(s)
- Shi-Wei Yue
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Hai-Ling Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Hong-Fei Su
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Chu Luo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Hui-Fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
| | - Bi-Xiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
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Qi YN, Liu Z, Hong LL, Li P, Ling ZQ. Methyltransferase-like proteins in cancer biology and potential therapeutic targeting. J Hematol Oncol 2023; 16:89. [PMID: 37533128 PMCID: PMC10394802 DOI: 10.1186/s13045-023-01477-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/10/2023] [Indexed: 08/04/2023] Open
Abstract
RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.
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Affiliation(s)
- Ya-Nan Qi
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, P.R. China
| | - Zhu Liu
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, P.R. China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, P.R. China
| | - Lian-Lian Hong
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, P.R. China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, P.R. China
| | - Pei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, P.R. China.
| | - Zhi-Qiang Ling
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, P.R. China.
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, P.R. China.
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44
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Deng X, Qing Y, Horne D, Huang H, Chen J. The roles and implications of RNA m 6A modification in cancer. Nat Rev Clin Oncol 2023; 20:507-526. [PMID: 37221357 DOI: 10.1038/s41571-023-00774-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 53.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2023] [Indexed: 05/25/2023]
Abstract
N6-Methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNA, has been extensively and increasingly studied over the past decade. Dysregulation of RNA m6A modification and its associated machinery, including writers, erasers and readers, is frequently observed in various cancer types, and the dysregulation profiles might serve as diagnostic, prognostic and/or predictive biomarkers. Dysregulated m6A modifiers have been shown to function as oncoproteins or tumour suppressors with essential roles in cancer initiation, progression, metastasis, metabolism, therapy resistance and immune evasion as well as in cancer stem cell self-renewal and the tumour microenvironment, highlighting the therapeutic potential of targeting the dysregulated m6A machinery for cancer treatment. In this Review, we discuss the mechanisms by which m6A modifiers determine the fate of target RNAs and thereby influence protein expression, molecular pathways and cell phenotypes. We also describe the state-of-the-art methodologies for mapping global m6A epitranscriptomes in cancer. We further summarize discoveries regarding the dysregulation of m6A modifiers and modifications in cancer, their pathological roles, and the underlying molecular mechanisms. Finally, we discuss m6A-related prognostic and predictive molecular biomarkers in cancer as well as the development of small-molecule inhibitors targeting oncogenic m6A modifiers and their activity in preclinical models.
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Affiliation(s)
- Xiaolan Deng
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
| | - Ying Qing
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA
| | - David Horne
- City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Huilin Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Jianjun Chen
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
- City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
- Gehr Family Center for Leukemia Research & City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
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45
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Li Z, Yang Z, Liu W, Zhu W, Yin L, Han Z, Xian Y, Wen J, Tang H, Lin X, Yang Y, Wang J, Zhang K. Disheveled3 enhanced EMT and cancer stem-like cells properties via Wnt/β-catenin/c-Myc/SOX2 pathway in colorectal cancer. J Transl Med 2023; 21:302. [PMID: 37147666 PMCID: PMC10161491 DOI: 10.1186/s12967-023-04120-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 04/09/2023] [Indexed: 05/07/2023] Open
Abstract
BACKGROUND Epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSLCs) play crucial role in tumor metastasis and drug-resistance. Disheveled3 (DVL3) is involved in malignant behaviors of cancer. However, the role and potential mechanism of DVL3 remain elusive in EMT and CSLCs of colorectal cancer (CRC). METHODS UALCAN and PrognoScan databases were employed to evaluate DVL3 expression in CRC tissues and its correlation with CRC prognosis, respectively. Transwell, sphere formation and CCK8 assay were used to assess metastasis, stemness and drug sensitivity of CRC cells, respectively. Western blotting and dual luciferase assay were performed to analyze the protein expression and Wnt/β-catenin activation, respectively. Lentiviral transfection was used to construct the stable cell lines. Animal studies were performed to analyze the effect of silencing DVL3 on tumorigenicity and metastasis of CRC cells in vivo. RESULTS DVL3 was overexpressed in CRC tissues and several CRC cell lines. DVL3 expression was also higher in CRC tissues with lymph node metastasis than tumor tissues without metastasis, and correlated with poor prognosis of CRC patients. DVL3 positively regulated the abilities of migration, invasion and EMT-like molecular changes in CRC cells. Moreover, DVL3 promoted CSLCs properties and multidrug resistance. We further identified that Wnt/β-catenin was crucial for DVL3-mediated EMT, stemness and SOX2 expression, while silencing SOX2 inhibited DVL3-mediated EMT and stemness. Furthermore, c-Myc, a direct target gene of Wnt/β-catenin, was required for SOX2 expression and strengthened EMT and stemness via SOX2 in CRC cells. Finally, knockdown of DVL3 suppressed tumorigenicity and lung metastasis of CRC cells in nude mice. CONCLUSION DVL3 promoted EMT and CSLCs properties of CRC via Wnt/β-catenin/c-Myc/SOX2 axis, providing a new strategy for successful CRC treatment.
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Affiliation(s)
- Zhengguang Li
- Oncology Department of Chengdu Seventh People's Hospital, Chengdu, China.
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China.
| | - Zhirong Yang
- Pathology Department of Deyang People's Hospital, Deyang, 618000, China
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Wei Liu
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 61051, China
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Wanglong Zhu
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Lan Yin
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Zhenyu Han
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Yu Xian
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Jie Wen
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Hualong Tang
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Xinyue Lin
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Yuhan Yang
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Jingyi Wang
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 61051, China.
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China.
| | - Kun Zhang
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 61051, China.
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China.
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46
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He J, Liu F, Zhang Z. Functions of N6-methyladenosine in cancer metabolism: from mechanism to targeted therapy. Biomark Res 2023; 11:40. [PMID: 37055798 PMCID: PMC10100159 DOI: 10.1186/s40364-023-00483-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 04/07/2023] [Indexed: 04/15/2023] Open
Abstract
N6-methyladenosine (m6A) is the most abundant modification of eukaryotic mRNA and is involved in almost every stage of RNA metabolism. The m6A modification on RNA has been demonstrated to be a regulator of the occurrence and development of a substantial number of diseases, especially cancers. Increasing evidence has shown that metabolic reprogramming is a hallmark of cancer and is crucial for maintaining the homeostasis of malignant tumors. Cancer cells rely on altered metabolic pathways to support their growth, proliferation, invasion and metastasis in an extreme microenvironment. m6A regulates metabolic pathways mainly by either directly acting on metabolic enzymes and transporters or indirectly influencing metabolism-related molecules. This review discusses the functions of the m6A modification on RNAs, its role in cancer cell metabolic pathways, the possible underlying mechanisms of its effects and the implication of this modification in cancer therapy.
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Affiliation(s)
- Jiayi He
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China.
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China.
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47
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Unraveling the function of epithelial-mesenchymal transition (EMT) in colorectal cancer: Metastasis, therapy response, and revisiting molecular pathways. Biomed Pharmacother 2023; 160:114395. [PMID: 36804124 DOI: 10.1016/j.biopha.2023.114395] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/03/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023] Open
Abstract
Colorectal cancer (CRC) is a dangerous form of cancer that affects the gastrointestinal tract. It is a major global health concern, and the aggressive behavior of tumor cells makes it difficult to treat, leading to poor survival rates for patients. One major challenge in treating CRC is the metastasis, or spread, of the cancer, which is a major cause of death. In order to improve the prognosis for patients with CRC, it is necessary to focus on ways to inhibit the cancer's ability to invade and spread. Epithelial-mesenchymal transition (EMT) is a process that is linked to the spread of cancer cells, also known as metastasis. The process transforms epithelial cells into mesenchymal ones, increasing their mobility and ability to invade other tissues. This has been shown to be a key mechanism in the progression of colorectal cancer (CRC), a particularly aggressive form of gastrointestinal cancer. The activation of EMT leads to increases in the spread of CRC cells, and during this process, levels of the protein E-cadherin decrease while levels of N-cadherin and vimentin increase. EMT also contributes to the development of resistance to chemotherapy and radiation therapy in CRC. Non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a role in regulating EMT in CRC, often through their ability to "sponge" microRNAs. Anti-cancer agents have been shown to suppress EMT and reduce the progression and spread of CRC cells. These findings suggest that targeting EMT or related mechanisms may be a promising approach for treating CRC patients in the clinic.
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Chen L, Gao Y, Xu S, Yuan J, Wang M, Li T, Gong J. N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms. Front Immunol 2023; 14:1162607. [PMID: 36999016 PMCID: PMC10043241 DOI: 10.3389/fimmu.2023.1162607] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 02/28/2023] [Indexed: 03/16/2023] Open
Abstract
As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m6A) is involved in a wide range of physiological and pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, and YTHDF3, are a class of cytoplasmic m6A-binding proteins defined by the vertebrate YTH domain, and exert extensive functions in regulating RNA destiny. Distinct expression patterns of the YTHDF family in specific cell types or developmental stages result in prominent differences in multiple biological processes, such as embryonic development, stem cell fate, fat metabolism, neuromodulation, cardiovascular effect, infection, immunity, and tumorigenesis. The YTHDF family mediates tumor proliferation, metastasis, metabolism, drug resistance, and immunity, and possesses the potential of predictive and therapeutic biomarkers. Here, we mainly summary the structures, roles, and mechanisms of the YTHDF family in physiological and pathological processes, especially in multiple cancers, as well as their current limitations and future considerations. This will provide novel angles for deciphering m6A regulation in a biological system.
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Affiliation(s)
- Lin Chen
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Gao
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Simiao Xu
- Division of Endocrinology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Branch of National Clinical Research Center for Metabolic Disease, Wuhan, China
| | - Jinxiong Yuan
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Wang
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianyu Li
- Trauma Center/Department of Emergency and Traumatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Gong
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jun Gong,
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Cao X, Geng Q, Fan D, Wang Q, Wang X, Zhang M, Zhao L, Jiao Y, Deng T, Liu H, Zhou J, Jia L, Xiao C. m 6A methylation: a process reshaping the tumour immune microenvironment and regulating immune evasion. Mol Cancer 2023; 22:42. [PMID: 36859310 PMCID: PMC9976403 DOI: 10.1186/s12943-022-01704-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 12/19/2022] [Indexed: 03/03/2023] Open
Abstract
N6-methyladenosine (m6A) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by m6A writers, erasers, and readers, m6A modulation is involved in myriad physiological and pathological processes. Extensive studies have demonstrated m6A modulation in diverse tumours, with effects on tumorigenesis, metastasis, and resistance. Recent evidence has revealed an emerging role of m6A modulation in tumour immunoregulation, and divergent m6A methylation patterns have been revealed in the tumour microenvironment. To depict the regulatory role of m6A methylation in the tumour immune microenvironment (TIME) and its effect on immune evasion, this review focuses on the TIME, which is characterized by hypoxia, metabolic reprogramming, acidity, and immunosuppression, and outlines the m6A-regulated TIME and immune evasion under divergent stimuli. Furthermore, m6A modulation patterns in anti-tumour immune cells are summarized.
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Affiliation(s)
- Xiaoxue Cao
- grid.415954.80000 0004 1771 3349Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China ,grid.506261.60000 0001 0706 7839Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Qishun Geng
- grid.415954.80000 0004 1771 3349Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China ,grid.506261.60000 0001 0706 7839Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Danping Fan
- grid.410318.f0000 0004 0632 3409Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qiong Wang
- grid.24695.3c0000 0001 1431 9176China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Xing Wang
- grid.24695.3c0000 0001 1431 9176China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Mengxiao Zhang
- grid.415954.80000 0004 1771 3349Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Lu Zhao
- grid.24696.3f0000 0004 0369 153XChina-Japan Friendship Hospital, Capital Medical University, Beijing, China
| | - Yi Jiao
- grid.24695.3c0000 0001 1431 9176China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Tingting Deng
- grid.415954.80000 0004 1771 3349Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Honglin Liu
- grid.415954.80000 0004 1771 3349Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Jing Zhou
- grid.256607.00000 0004 1798 2653Department of Physiology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi China
| | - Liqun Jia
- Oncology Department of Integrated Traditional Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, China.
| | - Cheng Xiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China. .,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China. .,Department of Emergency, China-Japan Friendship Hospital, Beijing, China.
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50
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Hedgehog-GLI and Notch Pathways Sustain Chemoresistance and Invasiveness in Colorectal Cancer and Their Inhibition Restores Chemotherapy Efficacy. Cancers (Basel) 2023; 15:cancers15051471. [PMID: 36900263 PMCID: PMC10000782 DOI: 10.3390/cancers15051471] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.
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