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Famà V, Coscujuela Tarrero L, Albanese R, Calviello L, Biffo S, Pelizzola M, Furlan M. Coupling mechanisms coordinating mRNA translation with stages of the mRNA lifecycle. RNA Biol 2025; 22:1-12. [PMID: 40116043 PMCID: PMC11934187 DOI: 10.1080/15476286.2025.2483001] [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: 12/29/2024] [Revised: 03/06/2025] [Accepted: 03/13/2025] [Indexed: 03/23/2025] Open
Abstract
Gene expression involves a series of consequential processes, beginning with mRNA synthesis and culminating in translation. Traditionally studied as a linear sequence of events, recent findings challenge this perspective, revealing coupling mechanisms that coordinate key steps of gene expression, even when spatially and temporally distant. In this review, we focus on translation, the final stage of gene expression, and examine its coupling with key stages of mRNA metabolism: synthesis, processing, export, and decay. For each of these processes, we provide an overview of known instances of coupling with translation. Furthermore, we discuss the role of high-throughput technologies in uncovering these intricate interactions on a genome-wide scale. Finally, we highlight key challenges and propose future directions to advance our understanding of how coupling mechanisms orchestrate robust and adaptable gene expression programs.
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Affiliation(s)
- Valeria Famà
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan, Italy
- Department of Oncology and Emato-Oncology, University of Milan, Milan, Italy
| | | | | | | | - Stefano Biffo
- National Institute of Molecular Genetics, Fondazione Romeo ed Enrica Invernizzi, INGM, Milan, Italy
- Department of Biosciences, University of Milan, Milan, Italy
| | - Mattia Pelizzola
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan, Italy
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Mattia Furlan
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan, Italy
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Liu X, Zhang L, Chen J, Shao W. Decoding intricate interactions between m6A modification with mRNAs and non-coding RNAs in cervical cancer: Molecular mechanisms and clinical implications. Cell Signal 2025; 131:111745. [PMID: 40107480 DOI: 10.1016/j.cellsig.2025.111745] [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: 10/10/2024] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
N6-methyladenosine (m6A) methylation is the most prevalent RNA modification that is regulated by three regulatory factors: "writers", "erasers" and "readers". m6A modification regulates RNA stability and other mechanisms, including translation, cleavage, and degradation. Current research has demonstrated that m6A methylation is involved in the regulation of occurrence and development of cancers by controlling the expression of cancer-related genes. This review summarizes the role of m6A modification on messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) in cervical cancer (CC). We highlight the dual role of m6A regulatory factors, which act as oncogenes or tumor suppressors depending on the cellular context and downstream targets. Additionally, we examine how ncRNAs reciprocally regulate m6A modification in two ways: by guiding the deposition or removal of m6A modifications on RNA targets, and by modulating the expression of m6A regulatory factors. These interactions further contribute to tumor progression. Furthermore, the therapeutic potential of targeting m6A modification has been emphasized in CC. Moreover, recent advances in small-molecule inhibitors targeting m6A regulators and RNA-based therapies which may offer new treatment strategies have been summarized. Finally, we discuss the current challenges in m6A modification research and provide suggestions for future research directions. This review aims to deepen the understanding of m6A modification in CC and contribute to the development of targeted and personalized treatment strategies.
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Affiliation(s)
- Xuefei Liu
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China; First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Lizhi Zhang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Ji Chen
- Department of Obstetrics, The Third Affiliated Hospital of Anhui Medical University, Hefei 230061, Anhui, China
| | - Wei Shao
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China.
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3
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Nakano T, Nakano M, Fukami T, Nakajima M. Cigarette smoking modulates m 6A modification, affecting the induction of CYP1A1 mRNA by regulating human ARNT and AHRR in A549 cells. Toxicol Lett 2025; 407:41-49. [PMID: 40118351 DOI: 10.1016/j.toxlet.2025.03.005] [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: 11/04/2024] [Revised: 02/23/2025] [Accepted: 03/17/2025] [Indexed: 03/23/2025]
Abstract
N6-Methyladenosine (m6A) modification is a common epitranscriptomic mark of eukaryotic RNAs. This modification is installed by a methyltransferase like 3 (METTL3)-METTL14 complex and is eliminated by fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5). Aberrant m6A modification is associated with the development and progression of cancer. Cigarette smoking is a major lifestyle habit and risk factor for lung cancer. This study aimed to clarify the effects of cigarette smoking on the expression of m6A modification-regulating enzymes and the significance of m6A modification in the biological responses to cigarette smoking. Treatment of cigarette smoke extract (CSE) significantly decreased METTL3 and METTL14 protein levels in human lung adenocarcinoma-derived A549 cells. The induction of CYP1A1 mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a typical ligand of the aryl hydrocarbon receptor (AHR), was attenuated by the knockdown (KD) of METTL3 or ALKBH5, whereas it was enhanced by the KD of FTO. As the underlying mechanisms, significantly decreased expression of AHR nuclear translocator (ARNT) by the KD of METTL3 or ALKBH5, and significantly decreased expression of AHR repressor (AHRR) by the KD of FTO were demonstrated. Formaldehyde-assisted isolation of regulatory elements assay revealed that the KD of METTL3 or ALKBH5 resulted in the compaction of the chromatin structure of ARNT promoter, suggesting that METTL3 and ALKBH5 promote the transcription of ARNT through the rearrangement of chromatin structure. Collectively, we found that CSE treatment decreased METTL3 and METTL14 protein levels, and m6A modification have impact on the induction of CYP1A1 by modulating ARNT and AHRR expression.
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Affiliation(s)
- Takumi Nakano
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Masataka Nakano
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Tatsuki Fukami
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Miki Nakajima
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
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Wu Z, Miao C, Zhang H. METTL3-mediated m6A modification in sepsis: current evidence and future perspectives. Epigenomics 2025:1-13. [PMID: 40251974 DOI: 10.1080/17501911.2025.2494983] [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: 12/25/2024] [Accepted: 04/15/2025] [Indexed: 04/21/2025] Open
Abstract
Sepsis, a severe systemic inflammatory condition triggered by infection, is associated with high morbidity and mortality worldwide. While medical diagnosis and treatment have advanced in recent years, a specific therapy remains unavailable. Recently, significant progress has been made in studying the epigenetic RNA modification N6-methyladenosine (m6A) and its core methyltransferase METTL3. The role of m6A in sepsis has also been increasingly elucidated. This review aims to explore the pathological mechanisms of sepsis and its relationship with m6A, focusing on the role of the key m6A writer, METTL3, in sepsis.
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Affiliation(s)
- Zijun Wu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hao Zhang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China
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Tang Y, Liu X, Ye W, Wang X, Wei X, Du Y, Zhang Y, Gong Y. METTL3, an Independent Adverse Prognostic Factor for AML, Promotes the Development of AML by Modulating the PGC-1α-MAPK Pathway and PGC-1α-Antioxidant System Axis. Cancer Med 2025; 14:e70771. [PMID: 40171845 PMCID: PMC11962650 DOI: 10.1002/cam4.70771] [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: 01/14/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 04/04/2025] Open
Abstract
BACKGROUND m6A represents a prevalent epigenetic modification of mammalian mRNAs. Studies have demonstrated that m6A RNA methylation-modifying enzymes play crucial roles in the onset and progression of AML. However, their clinical relevance remains undefined, and the mechanisms underlying their modulation of AML have yet to be elucidated. RESULTS The expression levels of the m6A RNA-modifying enzymes METTL3, METTL14, WTAP, FTO and ALKBH5 were elevated in AML patients. METTL3-positive AML is often accompanied by DNMT3A mutations and is also an independent poor prognostic factor for AML patients. Following METTL3 knockdown, we observed a decrease in the m6A level of the mitochondrial oxidative stress gene PGC-1α in K562 and MV4-11 cells. We analyzed the expression levels of PGC-1α and METTL3 mRNA in 105 patients with primary AML. The expression levels of PGC-1α and METTL3 mRNA were positively correlated. Similar to METTL3 knockdown, PGC-1α gene knockdown resulted in increased phosphorylation of the key signaling molecules P38, c-Jun and ERK1/2 in the MAPK signaling pathway, and decreased mRNA levels of SOD1, GPX1, catalase and UCP2 in the antioxidant system of K562 cells. Analysis of the TCGA and GSE13159 datasets, along with samples from West China Hospital, revealed that patients exhibiting high PGC-1α expression had a poor prognosis. CONCLUSION The m6A methylation-modifying enzyme METTL3 is an independent prognostic factor for poor prognosis in AML patients. PGC-1α is a downstream signaling molecule of METTL3, and METTL3 affects its expression by regulating the m6A level of PGC-1α. PGC-1α acts as an oncogene in AML by affecting the MAPK pathway and antioxidant system.
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Affiliation(s)
- Yuqian Tang
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xiaoyan Liu
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
- Department of HematologyFirst Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Wu Ye
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xiaojia Wang
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xiaoyu Wei
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Yiwen Du
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ying Zhang
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Yuping Gong
- Department of HematologyWest China Hospital, Sichuan UniversityChengduSichuanChina
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Wang J, Zhang Z, Shi F, Li Y, Shi C, Wang T, Sun L, Ao L, Han F, Chen Q, Cao J, Liu J. WTAP-mediated m 6A modification of Hmgb2 contributes to spermatogenic damage induced by PM 2.5 exposure. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 370:125896. [PMID: 39988248 DOI: 10.1016/j.envpol.2025.125896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/31/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
N6-methyladenosine (m6A) is extensively involved in complex spermatogenesis while being extremely sensitive to environmental exposure. Numerous studies have revealed the toxicity of fine particulate matter (PM2.5) to the male reproductive system, but the specific epigenetic mechanisms involved have been underexplored. Here, we investigated the effect of m6A modification on PM2.5-induced male reproductive impairment by establishing a real-time PM2.5-exposed mouse model and a GC-2spd cell model. PM2.5 exposure resulted in damage to the spermatogenic epithelium and mitochondrial abnormalities in spermatocytes and significantly reduced sperm motility in mice. Gene enrichment analyses of testicular tissue differential m6A modified genes were significantly enriched to spermatogenesis in the PM2.5-treated mice compared with the control group, and the expression of the methylase WTAP was markedly decreased after PM2.5 exposure. Moreover, PM2.5 exposure resulted in a significant reduction in the expression of the spermatogenesis-related gene Hmgb2, as well as in the level of the Hmgb2 m6A modification. Transcriptome sequencing and verification experiments suggested that Hmgb2 may regulate spermatocyte ATP levels. In addition, we demonstrated that the m6A methylase WTAP affects Hmgb2 mRNA stability via m6A modification. Our study provides new insights into PM2.5-induced damage to spermatogenesis and reduced sperm motility.
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Affiliation(s)
- Jiankang Wang
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China; Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Zhonghao Zhang
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China; Frontier Medical Training Brigade, Third Military Medical University, Xinjiang, 831200, China
| | - Fuquan Shi
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Yingqing Li
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Chaofeng Shi
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Tong Wang
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Lei Sun
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Lin Ao
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Fei Han
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Qing Chen
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Jia Cao
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China
| | - Jinyi Liu
- Institute of Toxicology, College of Preventive Medicine, State Key Lab of Trauma and Chemical Poisoning, Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Army Medical University, Chongqing, 400038, China.
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7
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Xiong Q, Zhang Y, Zheng Y, Zhu Q. Regulation and application of m 6A modification in tumor immunity. SCIENCE CHINA. LIFE SCIENCES 2025; 68:974-993. [PMID: 39648245 DOI: 10.1007/s11427-024-2648-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/11/2024] [Indexed: 12/10/2024]
Abstract
The m6A modification is an RNA modification that impacts various processes of RNA molecules, including transcription, splicing, stability, and translation. Recently, researchers have discovered that the presence of m6A modification can influence the interaction between tumor cells and immune cells and also play a role in regulating the expression of immune response-related genes. Additionally, m6A modification is intricately involved in the regulation of tumor immune evasion and drug resistance. Specifically, certain tumor cells can manipulate the gene expression through m6A modification to evade immune system attacks. Therefore, it might be possible to enhance tumor immune surveillance and improve the effectiveness of immune-based therapies by manipulating m6A modification. This review systematically discusses the role of m6A modification in tumor immunity, specifically highlighting its regulation of immune cells and immune-related genes in tumor cells. Furthermore, we explore the potential of m6A modification inhibitors as anti-cancer therapies and the significance of m6A regulatory factors in predicting the efficacy of tumor immune therapy.
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Affiliation(s)
- Qunli Xiong
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yaguang Zhang
- Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ying Zheng
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Sun N, Wang S, Liu J, Zhang P, Chang Y, Li H, Zhao K, Liu Y, Huang M, Hu Y, Lin Z, Lu Y, Jiang G, Chen W, Huang C, Jin H. XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1. Cell Death Dis 2025; 16:205. [PMID: 40133252 PMCID: PMC11937301 DOI: 10.1038/s41419-025-07545-9] [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: 06/06/2024] [Revised: 10/24/2024] [Accepted: 03/17/2025] [Indexed: 03/27/2025]
Abstract
X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 as its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced the expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of the MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.
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Affiliation(s)
- Ning Sun
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Sijia Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianting Liu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Peipei Zhang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yixin Chang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hongyan Li
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Kun Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yijie Liu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mingzhi Huang
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yan Hu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhenni Lin
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yongyong Lu
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guosong Jiang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Chen
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Chuanshu Huang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Honglei Jin
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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9
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Zhang X, Chen J, Zhou X, Zhou D, Liao L, Zhao Y, Wu P, Nie F, Liao Z, Cai Z, Duan X. Exploring diagnostic m6A regulators in primary open-angle glaucoma: insight from gene signature and possible mechanisms by which key genes function. BMC Med Genomics 2025; 18:57. [PMID: 40128732 PMCID: PMC11931807 DOI: 10.1186/s12920-025-02123-6] [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: 10/22/2024] [Accepted: 03/11/2025] [Indexed: 03/26/2025] Open
Abstract
PURPOSE The purpose of this study was to interrogate the potential role of N6-methyladenosine (m6A) regulators in the process of trabecular meshwork (TM) tissue damage in patients with primary open-angle glaucoma (POAG). METHODS Firstly, the expression profile of m6A regulators in TM tissues of POAG patients was comprehensively analyzed by bioinformatics analysis; Plasmid transfection and siRNA gene interference were used to enhance or weaken the expression levels of YTHDC2 in human trabecular meshwork cells (HTMCs); Cell migration ability was detected by transwell chamber assay; Immunofluorescence staining assay was used to evaluate the expression of extracellular matrix (ECM) related proteins. RESULTS Through the analysis of GSE27276 database, 5 m6A regulators with different expression in POAG were screened out. The results of random forest model showed that these 5 m6A regulators exhibited diagnostic potential and were characteristic genes of POAG. All POAG samples could be effectively divided into two groups based on the expression levels of these 5 hub m6A regulators. Immune cell infiltration analysis indicated that the levels of activated CD8+ T cells and regulatory T cells were different in the two subtypes. HTMC oxidative stress cell model and TGF-β2 stimulation cell model were further constructed to verify the expression of the aforementioned hub m6A regulators, and it was found that YTHDC2 mRNA showed the same expression trend in both models. The silencing of YTHDC2 enhanced the migration ability of HTMCs and increased the synthesis ability of ECM. However, when YTHDC2ΔYTH, which lacks the YTH domain, is overexpressed in HTMCs, there is no significant change in the ECM synthesis ability. CONCLUSIONS The differentially expressed m6A regulators in TM tissues may serve as potential diagnostic biomarkers for POAG. And, in HTMCs, the expression level of YTHDC2 mRNA was changed under oxidative stress or TGF-β2 intervention, and then exerted its regulation on cell migration and ECM synthesis capability through m6A modification, which may be an important part of the disease process of POAG.
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Affiliation(s)
- Xinyue Zhang
- Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Glaucoma Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Jiawei Chen
- Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Glaucoma Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Xiaoyu Zhou
- Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Glaucoma Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Dengming Zhou
- The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Liao
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Yang Zhao
- Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Glaucoma Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China
| | - Ping Wu
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Fen Nie
- Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Glaucoma Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China
| | - Zhimin Liao
- Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Glaucoma Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China
| | - Ziyan Cai
- Department of Ophthalmology, The Second Affiliated Hospital of Suzhou University, Suzhou, Jiangsu, China
| | - Xuanchu Duan
- Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Glaucoma Institute, Changsha Aier Eye Hospital, Changsha, Hunan, China.
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China.
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10
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Klausner MS, Greenberg CA, Noruzi KA, Tiwari RK, Geliebter J. The Role of M6A LncRNA Modification in Papillary Thyroid Cancer. Int J Mol Sci 2025; 26:2833. [PMID: 40243425 PMCID: PMC11988855 DOI: 10.3390/ijms26072833] [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: 07/04/2024] [Revised: 03/12/2025] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Abstract
Thyroid Cancer (TC) is the most common endocrine cancer, of which papillary thyroid cancer (PTC), a well-differentiated type of TC, accounts for 80-90%. Long non-coding RNAs (lncRNAs), which comprise non-protein-coding segments of the genome, have been found to play a crucial role in various biological processes, including cancer development. The activity of lncRNAs is modified through epigenetic modifications, with N6-Methyladenosine (m6A) modifications implicated in the progression of several malignancies. The activity of m6A is further regulated by modifying enzymes classified as "readers", writers", and "erasers", of which specific enzymes have been found to play a role in various aspects of PTC. Recent research has highlighted the significance of m6A modification in regulating the expression and function of lncRNAs associated with PTC pathogenesis. Dysregulation of this process implicates tumor proliferation, invasion, and metastasis, with subsequent impact on prognosis. Therefore, understanding the interplay between m6A modification and lncRNAs provides valuable insights into the molecular mechanisms underlying PTC progression. This narrative review aims to explore the established role of several prominent m6A modifying enzymes and lncRNAs on cancer pathogenesis and seeks to clarify the function of these enzymes in PTC pathogenesis.
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Affiliation(s)
| | - Caylee A. Greenberg
- School of Medicine, New York Medical College, Valhalla, NY 10595, USA; (M.S.K.)
| | - Kaleb A. Noruzi
- School of Medicine, New York Medical College, Valhalla, NY 10595, USA; (M.S.K.)
| | - Raj K. Tiwari
- Department of Pathology, Microbiology, and Immunology, and Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Jan Geliebter
- Department of Pathology, Microbiology, and Immunology, and Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
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11
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Liu Q, Yan L, Wu T, Wu Q, Ke B, Shen W. Peli1, regulated by m 6A modification, suppresses NLRP3 inflammasome activation in atherosclerosis by inhibiting YB-1. Commun Biol 2025; 8:457. [PMID: 40102597 PMCID: PMC11920095 DOI: 10.1038/s42003-025-07839-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 02/27/2025] [Indexed: 03/20/2025] Open
Abstract
The activation of pyrin domain-containing-3 (NLRP3) inflammasome in macrophages is a risk factor accelerating the progression of atherosclerosis (AS). Here, the function of pellino 1 (Peli1) in regulating the activation of NLRP3 inflammasome during the development of AS was investigated. Our results showed that Y-box binding protein 1 (YB-1) knockdown could inhibit the progression of AS in vivo, and YB-1 silencing repressed oxidized low-density lipoprotein (ox-LDL)-mediated lipid accumulation and inflammation in macrophages by inactivating NLRP3 inflammasome. E3 ubiquitination ligase Peli1 mediated ubiquitination-dependent degradation of YB-1 during AS progression. Moreover, it was found that YTH domain-containing 2 (YTHDC2) recognized methyltransferase-like 3 (METTL3)-mediated Peli1 N6-methyladenosine (m6A) modification and mediated Peli1 mRNA degradation. Rescue studies revealed that YB-1 upregulation abrogated the repressive effect of Peli1 upregulation on AS progression both in vitro and in vivo. Taken together, Peli1, regulated by m6A modification, inhibited YB-1-mediated activation of NLRP3 inflammasome in macrophages by promoting YB-1 ubiquitination to suppress the progression of AS.
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Affiliation(s)
- Qiang Liu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- Department of Cardiovascular Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Lu Yan
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Tao Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Ben Ke
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
| | - Wen Shen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
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12
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Zhou H, Shu R, Wu J, Zhou J, Yu Z, Cheng Q, Peng Z, Zhao M. Review of the role and potential clinical value of m6A methylation modifications in the biological process of osteosarcoma. Front Genet 2025; 16:1522622. [PMID: 40176793 PMCID: PMC11961878 DOI: 10.3389/fgene.2025.1522622] [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: 11/04/2024] [Accepted: 02/17/2025] [Indexed: 04/04/2025] Open
Abstract
Osteosarcoma (OS), an aggressive bone tumor, is a substantial threat to the quality of life and survival of affected individuals. Despite recent improvements in OS therapies, the considerable variability and chemotherapy resistance of this cancer necessitate continuous research to discover new treatment targets and biomarkers. Recent epigenetic advances highlight the crucial role of N6-methyladenosine (m6A) methylation in cancer. In OS, m6A methylation has been demonstrated to be a pivotal component in the pathogenesis. This review introduces new findings regarding the association between m6A methylation regulators and OS, and summarizes the potential clinical applications of OS and m6A methylation regulators, including the role of m6A methylation in OS proliferation, growth, apoptosis, and cell migration, invasion, and metastasis; relationship between m6A methylation and OS chemotherapy resistance; and relationship between m6A methylation and OS prognosis. Our review had certain limitations. The interaction between m6A methylation regulators and other oncogenic factors, such as lncRNAs and ncRNAs, is not fully understood. We hope that these potential methods will be translated into clinical applications and effective treatment.
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Affiliation(s)
- Huaqiang Zhou
- Department of orthopaedic surgery, Yingtan People’s Hospital, YingTan, China
| | - Rongbing Shu
- Department of orthopaedic surgery, Yingtan People’s Hospital, YingTan, China
| | - Jianming Wu
- Department of orthopaedic surgery, Yingtan People’s Hospital, YingTan, China
| | - Jiangjun Zhou
- Department of Orthopedic, The 908Th Hospital of Joint Logistic Support Force of PLA, Nanchang, China
| | - Zhuanyi Yu
- Department of orthopaedic surgery, Yingtan People’s Hospital, YingTan, China
| | - Qiuxin Cheng
- Department of orthopaedic surgery, Yingtan People’s Hospital, YingTan, China
| | - Zhihao Peng
- Department of orthopaedic surgery, Yingtan People’s Hospital, YingTan, China
| | - Min Zhao
- Department of orthopaedic surgery, Yingtan People’s Hospital, YingTan, China
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13
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Benak D, Alanova P, Holzerova K, Chalupova M, Opletalova B, Kolar F, Pavlinkova G, Hlavackova M. Epitranscriptomic regulation of HIF-1: bidirectional regulatory pathways. Mol Med 2025; 31:105. [PMID: 40102715 PMCID: PMC11917031 DOI: 10.1186/s10020-025-01149-x] [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: 01/27/2025] [Accepted: 03/03/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Epitranscriptomics, the study of RNA modifications such as N6-methyladenosine (m6A), provides a novel layer of gene expression regulation with implications for numerous biological processes, including cellular adaptation to hypoxia. Hypoxia-inducible factor-1 (HIF-1), a master regulator of the cellular response to low oxygen, plays a critical role in adaptive and pathological processes, including cancer, ischemic heart disease, and metabolic disorders. Recent discoveries accent the dynamic interplay between m6A modifications and HIF-1 signaling, revealing a complex bidirectional regulatory network. While the roles of other RNA modifications in HIF-1 regulation remain largely unexplored, emerging evidence suggests their potential significance. MAIN BODY This review examines the reciprocal regulation between HIF-1 and epitranscriptomic machinery, including m6A writers, readers, and erasers. HIF-1 modulates the expression of key m6A components, while its own mRNA is regulated by m6A modifications, positioning HIF-1 as both a regulator and a target in this system. This interaction enhances our understanding of cellular hypoxic responses and opens avenues for clinical applications in treating conditions like cancer and ischemic heart disease. Promising progress has been made in developing selective inhibitors targeting the m6A-HIF-1 regulatory axis. However, challenges such as off-target effects and the complexity of RNA modification dynamics remain significant barriers to clinical translation. CONCLUSION The intricate interplay between m6A and HIF-1 highlights the critical role of epitranscriptomics in hypoxia-driven processes. Further research into these regulatory networks could drive therapeutic innovation in cancer, ischemic heart disease, and other hypoxia-related conditions. Overcoming challenges in specificity and off-target effects will be essential for realizing the potential of these emerging therapies.
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Affiliation(s)
- Daniel Benak
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Petra Alanova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Kristyna Holzerova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Miloslava Chalupova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Barbora Opletalova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Frantisek Kolar
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Gabriela Pavlinkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic
| | - Marketa Hlavackova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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14
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Chen T, Ye W, Gao S, Li Y, Luan J, Lv X, Wang S. Emerging importance of m6A modification in liver cancer and its potential therapeutic role. Biochim Biophys Acta Rev Cancer 2025; 1880:189299. [PMID: 40088993 DOI: 10.1016/j.bbcan.2025.189299] [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: 10/24/2024] [Revised: 03/04/2025] [Accepted: 03/09/2025] [Indexed: 03/17/2025]
Abstract
Liver cancer refers to malignant tumors that form in the liver and is usually divided into several types, the most common of which is hepatocellular carcinoma (HCC), which originates in liver cells. Other rare types of liver cancer include intrahepatic cholangiocarcinoma (iCCA). m6A modification is a chemical modification of RNA that usually manifests as the addition of a methyl group to adenine in the RNA molecule to form N6-methyladenosine. This modification exerts a critical role in various biological processes by regulating the metabolism of RNA, affecting gene expression. Recent studies have shown that m6A modification is closely related to the occurrence and development of liver cancer, and m6A regulators can further participate in the pathogenesis of liver cancer by regulating the expression of key genes and the function of specific cells. In this review, we provided an overview of the latest advances in m6A modification in liver cancer research and explored in detail the specific functions of different m6A regulators. Meanwhile, we deeply analyzed the mechanisms and roles of m6A modification in liver cancer, aiming to provide novel insights and references for the search for potential therapeutic targets. Finally, we discussed the prospects and challenges of targeting m6A regulators in liver cancer therapy.
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Affiliation(s)
- Tao Chen
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Wufei Ye
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Songsen Gao
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province 230022, China
| | - Yueran Li
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Xiongwen Lv
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province 230032, China.
| | - Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province 230032, China.
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15
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Mao Z, Li M, Wang S. Targeting m 6A RNA Modification in Tumor Therapeutics. Curr Oncol 2025; 32:159. [PMID: 40136363 PMCID: PMC11941731 DOI: 10.3390/curroncol32030159] [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: 02/05/2025] [Revised: 02/27/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025] Open
Abstract
The prevalent eukaryotic RNA modification N6-methyladenosine (m6A), which is distributed in more than 50% of cases, has demonstrated significant implications in both normal development and disease progression, particularly in the context of cancer. This review aims to discuss the potential efficacy of targeting tumor cells through modulation of m6A RNA levels. Specifically, we discuss how the upregulation or downregulation of integral or specific targets is effective in treating different tumor types and patients. Additionally, we will cover the factors influencing the efficacy of m6A RNA targeting in tumor treatment. Our review will focus on the impact of targeting m6A mRNA on genes and cells and assess its potential as a therapeutic strategy for tumors. Despite the challenges involved, further research on m6A RNA in tumors and its integration with existing tumor therapy approaches is warranted.
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Affiliation(s)
- Zhenwei Mao
- Department of Laboratory Medicine, Affiliated People’s Hospital, Jiangsu University, Zhenjiang 212002, China
- Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212002, China
| | - Min Li
- Department of Laboratory Medicine, Affiliated People’s Hospital, Jiangsu University, Zhenjiang 212002, China
- Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212002, China
| | - Shengjun Wang
- Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212002, China
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
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16
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Weidle UH, Birzele F. Prostate Cancer: De-regulated Circular RNAs With Efficacy in Preclinical In Vivo Models. Cancer Genomics Proteomics 2025; 22:136-165. [PMID: 39993805 PMCID: PMC11880926 DOI: 10.21873/cgp.20494] [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: 11/14/2024] [Revised: 11/28/2025] [Accepted: 12/03/2024] [Indexed: 02/26/2025] Open
Abstract
Therapy resistance, including castration-resistance and metastasis, remains a major hurdle in the treatment of prostate cancer. In order to identify novel therapeutic targets and treatment modalities for prostate cancer, we conducted a comprehensive literature search on PubMed to identify de-regulated circular RNAs that influence treatment efficacy in preclinical prostate cancer-related in vivo models. Our analysis identified 49 circular RNAs associated with various processes, including treatment resistance, transmembrane and secreted proteins, transcription factors, signaling cascades, human antigen R, nuclear receptor binding, ubiquitination, metabolism, epigenetics and other target categories. The identified targets and circular RNAs can be further scrutinized through target validation approaches. Down-regulated circular RNAs are candidates for reconstitution therapy, while up-regulated RNAs can be inhibited using small interfering RNA (siRNA), antisense oligonucleotides (ASO) or clustered regularly interspaced short palindromic repeats/CRISPR associated (CRISPR-CAS)-related approaches.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany;
| | - Fabian Birzele
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
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17
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Tang J, Zhou C, Ye F, Zuo S, Zhou M, Lu L, Chai P, Fan X. RNA methylation homeostasis in ocular diseases: All eyes on Me. Prog Retin Eye Res 2025; 105:101335. [PMID: 39880118 DOI: 10.1016/j.preteyeres.2025.101335] [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: 07/28/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 01/31/2025]
Abstract
RNA methylation is a pivotal epigenetic modification that adjusts various aspects of RNA biology, including nuclear transport, stability, and the efficiency of translation for specific RNA candidates. The methylation of RNA involves the addition of methyl groups to specific bases and can occur at different sites, resulting in distinct forms, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), and 7-methylguanosine (m7G). Maintaining an optimal equilibrium of RNA methylation is crucial for fundamental cellular activities such as cell survival, proliferation, and migration. The balance of RNA methylation is linked to various pathophysiological conditions, including senescence, cancer development, stress responses, and blood vessel formation, all of which are pivotal for comprehending a spectrum of eye diseases. Recent findings have highlighted the significant role of diverse RNA methylation patterns in ophthalmological conditions such as age-related macular degeneration, diabetic retinopathy, cataracts, glaucoma, uveitis, retinoblastoma, uveal melanoma, thyroid eye disease, and myopia, which are critical for vision health. This thorough review endeavors to dissect the influence of RNA methylation on common and vision-impairing ocular disorders. It explores the nuanced roles that RNA methylation plays in key pathophysiological mechanisms, such as oxidative stress and angiogenesis, which are integral to the onset and progression of these diseases. By synthesizing the latest research, this review offers valuable insights into how RNA methylation could be harnessed for therapeutic interventions in the field of ophthalmology.
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Affiliation(s)
- Jieling Tang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China
| | - Chuandi Zhou
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China
| | - Fuxiang Ye
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China
| | - Sipeng Zuo
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China
| | - Min Zhou
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China
| | - Linna Lu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China.
| | - Peiwei Chai
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China.
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, State Key Laboratory of Vision Health, China.
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18
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Naderi N, Tavalaee M, Nasr-Esfahani MH. The epigenetic approach of varicocele: a focus on sperm DNA and m6A-RNA methylation. Hum Reprod Update 2025; 31:81-101. [PMID: 39673728 DOI: 10.1093/humupd/dmae034] [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: 07/15/2024] [Revised: 10/21/2024] [Indexed: 12/16/2024] Open
Abstract
BACKGROUND Varicocele is an abnormal dilation and torsion of the pampiniform venous plexus in the scrotum due to venous reflux, primarily affecting the left side. It affects 15% of men and is a prevalent contributor to male infertility. Varicocele is a complex disorder influenced by genetic, epigenetic, and environmental factors. Epigenetic modifications, which regulate genome activity independently of DNA or RNA sequences, may contribute to the development and severity of varicocele. These include DNA methylation, histone modifications, and RNA modifications like N6-methyladenosine (m6A). Irregularities in DNA and m6A-RNA methylation during spermatogenesis can cause gene expression abnormalities, DNA damage, and decreased fertility in varicocele patients. OBJECTIVE AND RATIONALE The review aims to comprehensively understand the underlying mechanisms of varicocele, a condition that can significantly impact male fertility. By exploring the role of methylation modifications, specifically DNA and m6A-RNA methylation, the review aims to synthesize evidence from basic, preclinical, and clinical research to expand the existing knowledge on this subject. The ultimate goal is to identify potential avenues for developing targeted treatments that can effectively improve varicocele and ultimately increase sperm quality in affected individuals. SEARCH METHODS A thorough investigation of the scientific literature was conducted through searches in PubMed, Google Scholar, and Science Direct databases until May 2024. All studies investigating the relationship between DNA and m6A-RNA methylation and male infertility, particularly varicocele were reviewed, and the most pertinent reports were included. Keywords such as varicocele, epigenetics, DNA methylation, m6A-RNA methylation, hypermethylation, hypomethylation, spermatozoa, semen parameters, spermatogenesis, and male infertility were used during the literature search, either individually or in combination. OUTCOMES The sperm has a specialized morphology essential for successful fertilization, and its epigenome is unique, potentially playing a key role in embryogenesis. Sperm DNA and RNA methylation, major epigenetic marks, regulate the expression of testicular genes crucial for normal spermatogenesis. This review explores the role of DNA and m6A-RNA methylation, in responding to oxidative stress and how various nutrients influence their function in varicocele condition. Evidence suggests a potential link between varicocele and aberrant DNA/m6A-RNA methylation patterns, especially hypomethylation, but the body of evidence is still limited. Further studies are needed to understand how abnormal expression of DNA/m6A-RNA methylation regulators affects testicular gene expression. Thus, analyzing sperm DNA 5mC/5hmC levels and m6A-RNA methylation regulators may reveal spermatogenesis defects and predict reproductive outcomes. WIDER IMPLICATIONS Nutri-epigenomics is an emerging field that could enhance the knowledge and management of diseases with unpredictable risks and consequences, even among individuals with similar lifestyles, by elucidating the influence of nutrition on DNA/m6A-RNA methylation through one-carbon metabolism. However, the importance of one-carbon metabolism to varicocele is not well-recognized. Health status and diet influence one-carbon metabolism and its associated DNA/m6A-RNA methylation modification. Future research should identify optimal methylation patterns that promote health and investigate modulating one-carbon metabolism to achieve this. Furthermore, additional studies are necessary to develop personalized dietary strategies through clinical and longitudinal research. However, a research gap exists on dietary interventions utilizing epigenetics as a therapeutic method for treating varicocele. REGISTRATION NUMBER Not applicable.
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Affiliation(s)
- Nushin Naderi
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Marziyeh Tavalaee
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
- Pooyesh & Rooyesh Fertility Center, Isfahan, Iran
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19
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Zhang L, Chen C, Feng J, Zhang H, Nguyen LXT, Chen Z. The role of YTHDF2 in anti-tumor immunity. CELL INVESTIGATION 2025; 1:100008. [PMID: 40092843 PMCID: PMC11908620 DOI: 10.1016/j.clnves.2025.100008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
RNA N 6-methyladenosine (m6A) modification has been identified as the most abundant RNA modification and plays crucial roles in both physiological and pathological processes. YTHDF2 was the first identified reader protein that can recognize m6A modification and recent studies also revealed its ability to bind 5-methylcytidine (m5C) modification. YTHDF2 shows a dual binding capacity to both m6A and m5C, which leads to opposite mRNA outcomes. Multiple studies have highlighted the critical roles of YTHDF2 in tumor development and tumor microenvironment. Emerging findings showed that YTHDF2 plays critical roles in immune regulation, impacting T cell, B cell, NK cell, macrophage, innate/adaptive anti-tumor immune responses, and T-cell based immunotherapy. Inhibitors have been developed to target YTHDF2, which showed potential efficacy in tumor treatment. Herein, we reviewed the molecular mechanism of YTHDF2 and its roles in tumors, immune cells, and tumor microenvironment.
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Affiliation(s)
- Lianjun Zhang
- Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Cunte Chen
- Department of Hematology, Guangzhou First People's Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical University, Guangzhou 510180, China
| | - Jia Feng
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Hongyu Zhang
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Le Xuan Truong Nguyen
- Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute, Phoenix, AZ 85004 USA
| | - Zhenhua Chen
- Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Department of Hematology, The First Affiliated Hospital; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, China
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20
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Chen H, Xuan A, Shi X, Fan T, Xue S, Ruan J, Wang X, Tang S, Qi W, Sun H, Liu C, He S, Ding C, Zhu Z. RNA N6-methyladenosine modification in arthritis: New insights into pathogenesis. Mod Rheumatol 2025; 35:203-214. [PMID: 39235765 DOI: 10.1093/mr/roae080] [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: 01/22/2024] [Accepted: 08/15/2024] [Indexed: 09/06/2024]
Abstract
The commonest type of eukaryotic RNA modification, N6-methyladenosine (m6A), has drawn increased scrutiny in the context of pathological functioning as well as relevance in determination of RNA stability, splicing, transportation, localization, and translation efficiency. The m6A modification plays an important role in several types of arthritis, especially osteoarthritis and rheumatoid arthritis. Recent studies have reported that m6A modification regulates arthritis pathology in cells, such as chondrocytes and synoviocytes via immune responses and inflammatory responses through functional proteins classified as writers, erasers, and readers. The aim of this review was to highlight recent advances relevant to m6A modification in the context of arthritis pathogenesis and detail underlying molecular mechanisms, regulatory functions, clinical applications, and future perspectives of m6A in arthritis with the aim of providing a foundation for future research directions.
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Affiliation(s)
- Haowei Chen
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Anran Xuan
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaorui Shi
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Tianxiang Fan
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Song Xue
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianzhao Ruan
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoshuai Wang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Su'an Tang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Weizhong Qi
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Canzhao Liu
- Department of Cardiovascular Medicine, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shuai He
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Changhai Ding
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Rheumatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Zhaohua Zhu
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Rheumatology, Royal North Shore Hospital and Sydney Musculoskeletal Health, Kolling Institute, University of Sydney, Sydney, Australia
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21
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Wen J, Li A, Wang Z, Guo X, Zhang G, Litzow MR, Liu Q. Hepatotoxicity induced by arsenic trioxide: clinical features, mechanisms, preventive and potential therapeutic strategies. Front Pharmacol 2025; 16:1536388. [PMID: 40051569 PMCID: PMC11882591 DOI: 10.3389/fphar.2025.1536388] [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: 11/28/2024] [Accepted: 01/27/2025] [Indexed: 03/09/2025] Open
Abstract
Arsenic trioxide (ATO) has shown substantial efficacy in the treatment of patients with acute promyelocytic leukemia, and the utilization of ATO as a potential treatment for other tumors is currently being investigated; thus, its clinical application is becoming more widespread. However, the toxicity of ATO has prevented many patients from receiving this highly beneficial treatment. The clinical features, mechanisms, and preventive measures for ATO hepatotoxicity, as well as potential curative strategies, are discussed in this review. This review not only discusses existing drugs for the treatment of hepatotoxicity but also focuses on potential future therapeutic agents, providing forward-looking guidance for the clinical use of small molecule extracts, trace elements, antidiabetic drugs, and vitamins.
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Affiliation(s)
- Jun Wen
- Department of Haematology, Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Aiwen Li
- Department of Haematology, Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Ziliang Wang
- Department of Haematology, Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Xiaoxiao Guo
- Department of Haematology, Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Gaoling Zhang
- Center of Hematology, Peking University People’s Hospital Qingdao, Qingdao, China
| | - Mark R. Litzow
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Qiuju Liu
- Department of Haematology, Cancer Center, The First Hospital of Jilin University, Changchun, China
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22
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Wang L, Weichselbaum RR, He C. N 6-methyladenosine reader YTHDF2 in cell state transition and antitumor immunity. RNA (NEW YORK, N.Y.) 2025; 31:395-401. [PMID: 39719324 PMCID: PMC11874973 DOI: 10.1261/rna.080259.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/16/2024] [Indexed: 12/26/2024]
Abstract
Recent studies have revealed that the YTHDF family proteins bind preferentially to the N 6-methyladenosine (m6A)-modified mRNA and regulate the functions of these RNAs in different cell types. YTHDF2, the first identified m6A reader in mammals, has garnered significant attention because of its profound effect to regulate the m6A epitranscriptome in multiple biological processes. Here, we review current knowledge on the mechanisms by which YTHDF2 exerts its functions and discuss recent advances that underscore the multifaceted role of YTHDF2 in development, stem cell expansion, and immune evasion. We also highlight potential therapeutic interventions targeting the m6A/YTHDF2 axis to improve the response to current antitumor therapies.
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Affiliation(s)
- Liangliang Wang
- The Laboratory of Microbiome and Microecological Technology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Ralph R Weichselbaum
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 60637, USA
- Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois 60637, USA
| | - Chuan He
- Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, USA
- Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois 60637, USA
- Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA
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23
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Shen R, Jiang Z, Wang H, Zheng Z, Jiang X. Molecular mechanisms of m6A modifications regulating tumor radioresistance. Mol Med 2025; 31:64. [PMID: 39972266 PMCID: PMC11837317 DOI: 10.1186/s10020-025-01121-9] [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: 08/01/2024] [Accepted: 02/07/2025] [Indexed: 02/21/2025] Open
Abstract
Radiotherapy is one of the most effective treatments for malignant tumors. Radioresistance is a major factor that contributes to radiotherapy failure and poor prognosis. Recent studies have elucidated the pivotal role of aberrant N6-methyladenosine (m6A) modification, the predominant internal mRNA modification in eukaryotic cells, influences cancer progression by disrupting gene expression and other critical cellular processes. Furthermore, aberrant m6A methylation provides a substrate for tumor therapy; however, whether it regulates tumor radioresistance remains unclear. Methylated transferase (writer), demethylated transferase (eraser), and methylated recognition protein (reader) are the three essential proteins that regulate m6A modification via different mechanisms in different tumors. This review summarizes the latest research advances in m6A methylation and aims to provide novel perspectives on the advancement of regimens to overcome radioresistance and tumor invasion.
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Affiliation(s)
- Ruolin Shen
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Zhenyang Jiang
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Huanhuan Wang
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Zhuangzhuang Zheng
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Xin Jiang
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China.
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China.
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24
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Rong H, Jiang Y. METTL14 suppresses the migration and invasion of hepatocellular carcinoma cells by m6A methylation of RPLP2. Sci Rep 2025; 15:5660. [PMID: 39955344 PMCID: PMC11830075 DOI: 10.1038/s41598-025-87701-5] [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: 08/07/2024] [Accepted: 01/21/2025] [Indexed: 02/17/2025] Open
Abstract
Fluctuating N(6)-methyladenosine (m6A) levels affect the progression of hepatocellular carcinoma (HCC). METTL14, a m6A methyltransferase, acts as a tumor suppressor in HCC; however, its underlying mechanisms need further clarification. This study aimed to clarify the role of METTL14 in HCC and the underlying molecular mechanism. Cellular behaviors were evaluated using cell counting kit-8, EdU, and Transwell assays. The molecular mechanism was analyzed using methylated RNA binding protein immunoprecipitation, dual-luciferase reporter assay, and RNA stability determination. The results demonstrated that METTL14 expression was decreased in HCC tissues and cells, and its overexpression suppressed cellular proliferation, migration, and invasion. Moreover, RPLP2 was negatively correlated to METTL14, and it was highly expressed in HCC tissues and cells. METTL14 promoted the m6A modification of RPLP2 and reduced its stability, thereby inhibiting malignant behaviors. Besides, YTHDC2 decreased RPLP2 expression and reversed the stability induced by METTL14. In conclusion, METTL14 inhibits HCC progression by regulating the YTHDC2-m6A-RPLP2 axis.
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Affiliation(s)
- Haiyan Rong
- Laboratory Medicine Diagnostic Centre, The First Affiliated Hospital, Xinjiang Medical University, No.118, Liyushan Road, Xinshi District, Urumqi, 830011, Xinjiang, China
| | - Yan Jiang
- Laboratory Medicine Diagnostic Centre, The First Affiliated Hospital, Xinjiang Medical University, No.118, Liyushan Road, Xinshi District, Urumqi, 830011, Xinjiang, China.
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25
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Ge L, Pan F, Jia M, Pott DM, He H, Shan H, Lozano-Durán R, Wang A, Zhou X, Li F. RNA modifications in plant biotic interactions. PLANT COMMUNICATIONS 2025; 6:101232. [PMID: 39722456 PMCID: PMC11897454 DOI: 10.1016/j.xplc.2024.101232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024]
Abstract
The chemical modifications of DNA and proteins are powerful mechanisms for regulating molecular and biological functions, influencing a wide array of signaling pathways in eukaryotes. Recent advancements in epitranscriptomics have shown that RNA modifications play crucial roles in diverse biological processes. Since their discovery in the 1970s, scientists have sought to decipher, identify, and elucidate the functions of these modifications across biological systems. Over the past decade, mounting evidence has demonstrated the importance of RNA modification pathways in plants, prompting significant efforts to decipher their physiological relevance. With the advent of high-resolution mapping techniques for RNA modifications and the gradual uncovering of their biological roles, our understanding of this additional layer of regulation is beginning to take shape. In this review, we summarize recent findings on the major RNA modifications identified in plants, with an emphasis on N6-methyladenosine (m6A), the most extensively studied modification. We discuss the functional significance of the effector components involved in m6A modification and its diverse roles in plant biotic interactions, including plant-virus, plant-bacterium, plant-fungus, and plant-insect relationships. Furthermore, we highlight new technological developments driving research progress in this field and outline key challenges that remain to be addressed.
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Affiliation(s)
- Linhao Ge
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Fuan Pan
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; State Key Laboratory of Rice Biology, Institute of Biotechnology, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Mingxuan Jia
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Delphine M Pott
- Department of Plant Biochemistry, Centre for Plant Molecular Biology (ZMBP), Eberhard Karls University, 72076 Tübingen, Germany
| | - Hao He
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Hongying Shan
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Rosa Lozano-Durán
- Department of Plant Biochemistry, Centre for Plant Molecular Biology (ZMBP), Eberhard Karls University, 72076 Tübingen, Germany
| | - Aiming Wang
- London Research and Development Centre, Agriculture and Agri-Food Canada, London, ON N5V 4T3, Canada
| | - Xueping Zhou
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; State Key Laboratory of Rice Biology, Institute of Biotechnology, Zhejiang University, Hangzhou, Zhejiang 310058, China.
| | - Fangfang Li
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
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Zhang Y, Wang Y, Peng J, Zhao K, Li L, Zhang Y, Zhai Z, Yuan S, Li S, Ye F, Wang L. Expression and prognostic significance of the m6A RNA methylation regulator HNRNPC in HNSCC. Front Oncol 2025; 15:1516867. [PMID: 39990687 PMCID: PMC11842334 DOI: 10.3389/fonc.2025.1516867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 01/17/2025] [Indexed: 02/25/2025] Open
Abstract
Background N6-methyladenosine (m6A) RNA modification is crucial for tumor development and progression; however, which m6A regulators play a pivotal role in head and neck squamous cell carcinoma (HNSCC) remains ambiguous. Methods Utilizing the Cancer Genome Atlas (TCGA) database, the expression levels of m6A regulators in HNSCC were examined, which led to the identification of heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a key gene. Further experiments were performed in patient samples, stable cell lines, and a murine xenograft tumor model. Results A reliable survival risk model of m6A was constructed based on the TCGA database. Gene Expression Omnibus (GEO), normal and tumor tissue microarrays (TMA), and tumor tissue samples from patients with HNSCC were observed that a high level of HNRNPC expression was closely linked to a poor prognosis among patients. Knockdown of HNRNPC in the HNSCC cell lines HSC-3 and CAL-27 resulted in a significant decrease in proliferation, invasion, and malignant transformation abilities. RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation and sequencing (MeRIP-seq) data revealed that HNRNPC is involved in cell differentiation, cell migration and apoptosis. The mouse xenograft model elucidated that HNRNPC can promote tumorigenesis and progression of HNSCC. Conclusions HNRNPC can serve as a valuable predictor of tumor progression and prognosis in patients with HNSCC.
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Affiliation(s)
- Yulin Zhang
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yixu Wang
- Department of Otolaryngology, Head and Neck Surgery, People’s Hospital, Peking University, Beijing, China
| | - Jilin Peng
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Zhao
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Li
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuan Zhang
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ziyu Zhai
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sijie Yuan
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shichao Li
- Department of Otolaryngology Head and Neck Surgery, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
- Department of Otolaryngology Head and Neck Surgery, People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Otolaryngology Head and Neck Surgery, People’s Hospital of Henan University, Zhengzhou, Henan, China
| | - Fanglei Ye
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Le Wang
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Li P, Lin Y, Ma H, Zhang J, Zhang Q, Yan R, Fan Y. Epigenetic regulation in female reproduction: the impact of m6A on maternal-fetal health. Cell Death Discov 2025; 11:43. [PMID: 39904996 PMCID: PMC11794895 DOI: 10.1038/s41420-025-02324-z] [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: 09/02/2024] [Revised: 01/09/2025] [Accepted: 01/24/2025] [Indexed: 02/06/2025] Open
Abstract
With the development of public health, female diseases have become the focus of current concern. The unique reproductive anatomy of women leads to the development of gynecological diseases gradually become an important part of the socio-economic burden. Epigenetics plays an irreplaceable role in gynecologic diseases. As an important mRNA modification, m6A is involved in the maturation of ovum cells and maternal-fetal microenvironment. At present, researchers have found that m6A is involved in the regulation of gestational diabetes and other reproductive system diseases, but the specific mechanism is not clear. In this manuscript, we summarize the components of m6A, the biological function of m6A, the progression of m6A in the maternal-fetal microenvironment and a variety of gynecological diseases as well as the progression of targeted m6A treatment-related diseases, providing a new perspective for clinical treatment-related diseases.
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Affiliation(s)
- Peipei Li
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Yumeng Lin
- Health Management Center, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hongyun Ma
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Jiao Zhang
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Qiaorui Zhang
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Ruihua Yan
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Yang Fan
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China.
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Tang W, Kong X, He S, Deng J, Mao M, Peng S, Song C. WTAP Regulates SOX1 Expression to Affect the Tumorigenicity of Colorectal Cancer via an m 6A-YTHDF2-Dependent Manner. Dig Dis Sci 2025; 70:598-611. [PMID: 39681745 PMCID: PMC11839869 DOI: 10.1007/s10620-024-08780-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND Wilms tumor 1-associated protein (WTAP) plays a critical role in various cancers, including colorectal cancer (CRC). However, the biological function and molecular mechanisms of WTAP in CRC remain to be elucidated. METHODS We determined the expression of WTAP and its correlation with unfavorable prognosis of CRC using RNA-seq and the UALCAN dataset. And we investigated the effects of WTAP on CRC cells using cell proliferation assay, colony formation, cell migration and invasion, and subcutaneous xenograft experiments. We then knockdown of WTAP to identify candidate targets of WTAP. Moreover, the mRNA stability of SRY-box transcription factor 1 (SOX1) was assessed by overexpressing YTHDF2. Finally, we investigated the regulatory mechanism of WTAP in CRC by MeRIP assay, RNA pulldown, dual-luciferase reporter assay, and RIP assay. RESULTS We demonstrated that CRC patients with a high expression of WTAP have a risk prognosis. Additionally, WTAP expression can serve as a predictor of survival in CRC. WTAP promoted the proliferation and tumor growth of CRC cells. Moreover, WTAP has been recognized as the upstream regulator of SOX1. WTAP regulated the m6A modification, resulting in the post-transcriptional inhibition of SOX1. YTHDF2 plays a role in promoting mRNA degradation. Then, SOX1 can hinder the progression of CRC. Furthermore, WTAP can regulate the proliferation, migration, and invasion of CRC cells by SOX1 via an m6A-YTHDF2-dependent manner. CONCLUSION Our findings demonstrate that WTAP-mediated m6A modification facilitated the progression of CRC through the YTHDF2-SOX1 axis and could serve as a potential therapeutic targeting for CRC.
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Affiliation(s)
- Wei Tang
- Department of Oncology, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Changsha City, Hunan Province, China
| | - Xian Kong
- Department of Oncology, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Changsha City, Hunan Province, China
| | - Shoushu He
- Department of Oncology, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Changsha City, Hunan Province, China
| | - Jing Deng
- Centre for Integrated Traditional Chinese and Western Medicine, Hunan Cancer Hospital, No. 283, Tongzipo Road, Yuelu District, Changsha City, Hunan Province, China
| | - Min Mao
- Centre for Integrated Traditional Chinese and Western Medicine, Hunan Cancer Hospital, No. 283, Tongzipo Road, Yuelu District, Changsha City, Hunan Province, China
| | - Siyuan Peng
- Centre for Integrated Traditional Chinese and Western Medicine, Hunan Cancer Hospital, No. 283, Tongzipo Road, Yuelu District, Changsha City, Hunan Province, China
| | - Cheng Song
- Centre for Integrated Traditional Chinese and Western Medicine, Hunan Cancer Hospital, No. 283, Tongzipo Road, Yuelu District, Changsha City, Hunan Province, China.
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29
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Kim HS, Eun JW, Jang SH, Kim JY, Jeong JY. The diverse landscape of RNA modifications in cancer development and progression. Genes Genomics 2025; 47:135-155. [PMID: 39643826 DOI: 10.1007/s13258-024-01601-y] [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: 10/25/2024] [Accepted: 11/22/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND RNA modifications, a central aspect of epitranscriptomics, add a regulatory layer to gene expression by modifying RNA function without altering nucleotide sequences. These modifications play vital roles across RNA species, influencing RNA stability, translation, and interaction dynamics, and are regulated by specific enzymes that add, remove, and interpret these chemical marks. OBJECTIVE This review examines the role of aberrant RNA modifications in cancer progression, exploring their potential as diagnostic and prognostic biomarkers and as therapeutic targets. We focus on how altered RNA modification patterns impact oncogenes, tumor suppressor genes, and overall tumor behavior. METHODS We performed an in-depth analysis of recent studies and advances in RNA modification research, highlighting key types and functions of RNA modifications and their roles in cancer biology. Studies involving preclinical models targeting RNA-modifying enzymes were reviewed to assess therapeutic efficacy and potential clinical applications. RESULTS Aberrant RNA modifications were found to significantly influence cancer initiation, growth, and metastasis. Dysregulation of RNA-modifying enzymes led to altered gene expression profiles in oncogenes and tumor suppressors, correlating with tumor aggressiveness, patient outcomes, and response to immunotherapy. Notably, inhibitors of these enzymes demonstrated potential in preclinical models by reducing tumor growth and enhancing the efficacy of existing cancer treatments. CONCLUSIONS RNA modifications present promising avenues for cancer diagnosis, prognosis, and therapy. Understanding the mechanisms of RNA modification dysregulation is essential for developing targeted treatments that improve patient outcomes. Further research will deepen insights into these pathways and support the clinical translation of RNA modification-targeted therapies.
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Affiliation(s)
- Hyung Seok Kim
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, 16499, South Korea
| | - Se Ha Jang
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, 16499, South Korea
| | - Ji Yun Kim
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea.
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30
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Zhang H, Lu W, Tang H, Chen A, Gao X, Zhu C, Zhang J. Novel Insight of N6-Methyladenosine in Cardiovascular System. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:222. [PMID: 40005339 PMCID: PMC11857502 DOI: 10.3390/medicina61020222] [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: 11/28/2024] [Revised: 01/19/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025]
Abstract
N6-methyladenosine (m6A) is the most common and abundant internal co-transcriptional modification in eukaryotic RNAs. This modification is catalyzed by m6A methyltransferases, known as "writers", including METTL3/14 and WTAP, and removed by demethylases, or "erasers", such as FTO and ALKBH5. It is recognized by m6A-binding proteins, or "readers", such as YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPA2B1. Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Recent studies indicate that m6A RNA modification plays a critical role in both the physiological and pathological processes involved in the initiation and progression of CVDs. In this review, we will explore how m6A RNA methylation impacts both the normal and disease states of the cardiovascular system. Our focus will be on recent advancements in understanding the biological functions, molecular mechanisms, and regulatory factors of m6A RNA methylation, along with its downstream target genes in various CVDs, such as atherosclerosis, ischemic diseases, metabolic disorders, and heart failure. We propose that the m6A RNA methylation pathway holds promise as a potential therapeutic target in cardiovascular disease.
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Affiliation(s)
- Huan Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Wei Lu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Haoyue Tang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Aiqun Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Xiaofei Gao
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
| | - Congfei Zhu
- Department of Cardiology, Lianshui County People’s Hospital, Affiliated Hospital of Kangda College, Nanjing Medical University, Huaian 223400, China
| | - Junjie Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (H.Z.); (W.L.); (H.T.); (A.C.); (X.G.)
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Yang Y, Ni WJ, Yang Y, Liao J, Yang Y, Li J, Zhu X, Guo C, Xie F, Leng XM. Research progress on N6-methyladenosine RNA modification in osteosarcoma: functions, mechanisms, and potential clinical applications. Med Oncol 2025; 42:55. [PMID: 39853585 DOI: 10.1007/s12032-024-02597-x] [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: 08/25/2024] [Accepted: 12/30/2024] [Indexed: 01/26/2025]
Abstract
Osteosarcoma (OS) is the most commonly diagnosed primary malignant bone tumor in children and adolescents. Despite significant advancements in therapeutic strategies against OS over the past few decades, the prognosis for this disease remains poor, largely due to its high invasiveness and challenges associated with its treatment. N6-methyladenosine (m6A) modification is one of the most abundant epigenetic modifications of RNAs, and many studies have highlighted its crucial role in OS. This article provides a comprehensive summary and introduction to m6A regulators, including methyltransferases, demethylases, and binding proteins. The article emphasizes how regulated m6A modifications can either promote or inhibit OS. It also delves into the mechanisms by which m6A-modified messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs) participate in signaling pathways such as the Wnt/β-catenin, PI3K/AKT, and STAT3 pathways, and discusses these mechanisms in detail. Given the abnormal expression of m6A regulators in OS, the article also explores their potential applications as biomarkers or therapeutic targets in clinical settings. It is anticipated that this review will provide new insights into the diagnosis and treatment of OS.
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Affiliation(s)
- Ying Yang
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Wen-Juan Ni
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Yadong Yang
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Junnan Liao
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Yuqian Yang
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Jianwei Li
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Xiuzhi Zhu
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Chun Guo
- Modern Industrial College of Biomedicine and Great Health, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Youjiang District, Baise, 533000, Guangxi, China
- Department of Human Anatomy, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Youjiang District, Baise, 533000, Guangxi, People's Republic of China
| | - Fuhua Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Xiao-Min Leng
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China.
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, China.
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Cheng Y, Shang Y, Zhang S, Fan S. The interplay between RNA m6A modification and radiation biology of cancerous and non-cancerous tissues: a narrative review. Cancer Biol Med 2025; 21:j.issn.2095-3941.2024.0415. [PMID: 39831771 PMCID: PMC11745087 DOI: 10.20892/j.issn.2095-3941.2024.0415] [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: 09/24/2024] [Accepted: 12/06/2024] [Indexed: 01/22/2025] Open
Abstract
The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues. Radiation therapy (RT) induces oncological responses, from molecular to phenotypic alterations, while simultaneously exerting toxic effects on healthy tissue. N6-methyladenosine (m6A), a prevalent modification on coding and non-coding RNAs, is a key epigenetic mark established by a set of evolutionarily conserved enzymes. The interplay between m6A modification and radiobiology of cancerous and non-cancerous tissues merits in-depth investigation. This review summarizes the roles of m6A in the biological effects induced by ionizing radiation and ultraviolet (UV) radiation. It begins with an overview of m6A modification and its detection methods, followed by a detailed examination of how m6A dynamically regulates the sensitivity of cancerous tissues to RT, the injury response in non-cancerous tissues, and the toxicological effects of UV exposure. Notably, this review underscores the importance of novel regulatory mechanisms of m6A and their potential clinical applications in identifying epigenetically modulated radiation-associated biomarkers for cancer therapy and estimation of radiation dosages. In conclusion, enzyme-mediated m6A-modification triggers alterations in target gene expression by affecting the metabolism of the modified RNAs, thus modulating progression and radiosensitivity in cancerous tissues, as well as radiation effects on normal tissues. Several promising avenues for future research are further discussed. This review highlights the importance of m6A modification in the context of radiation biology. Targeting epi-transcriptomic molecules might potentially provide a novel strategy for enhancing the radiosensitivity of cancerous tissues and mitigating radiation-induced injury to normal tissues.
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Affiliation(s)
- Yajia Cheng
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Yue Shang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Shuqin Zhang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Saijun Fan
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
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Xie X, Fang Z, Zhang H, Wang Z, Li J, Jia Y, Shang L, Cao F, Li F. The role of N(6)-methyladenosine (m6a) modification in cancer: recent advances and future directions. EXCLI JOURNAL 2025; 24:113-150. [PMID: 39967906 PMCID: PMC11830918 DOI: 10.17179/excli2024-7935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 12/18/2024] [Indexed: 02/20/2025]
Abstract
N(6)-methyladenosine (m6A) modification is the most abundant and prevalent internal modification in eukaryotic mRNAs. The role of m6A modification in cancer has become a hot research topic in recent years and has been widely explored. m6A modifications have been shown to regulate cancer occurrence and progression by modulating different target molecules. This paper reviews the recent research progress of m6A modifications in cancer and provides an outlook on future research directions, especially the development of molecularly targeted drugs. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Xiaozhou Xie
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zhen Fang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Haoyu Zhang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zheng Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jie Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yuchen Jia
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Liang Shang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Feng Cao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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34
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Li Z, Meng K, Lan S, Ren Z, Lai Z, Ao X, Liu Z, Xu J, Mo X, Zhang Z. The Role of mRNA Modifications in Bone Diseases. Int J Biol Sci 2025; 21:1065-1080. [PMID: 39897026 PMCID: PMC11781163 DOI: 10.7150/ijbs.104460] [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: 09/30/2024] [Accepted: 12/24/2024] [Indexed: 02/04/2025] Open
Abstract
As a type of epigenetic modifications, mRNA modifications regulate the metabolism of mRNAs, thereby influencing gene expression. Previous studies have indicated that dysregulation of mRNA modifications is closely associated with the occurrence and progression of bone diseases (BDs). In this study, we first introduced the dynamic regulatory processes of five major mRNA modifications and their effects on the nucleus export, stability, and translation of mRNAs. We then summarized the mechanisms of mRNA modifications involved in the development of osteoporosis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, fractures, osteomyelitis, and osteosarcoma. Finally, we reviewed therapeutic strategies for BDs based on the above mechanisms, focusing on regulating osteoblast and osteoclast differentiation, inhibiting cellular senescence and injury, and alleviating inflammation. This review identified mRNA modifications as potential targets for treating BDs and proposes perspectives on the diversity, targetability, and safety of mRNA-modifying therapies.
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Affiliation(s)
| | | | | | | | | | | | | | - Jiajia Xu
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Xiaoyi Mo
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Zhongmin Zhang
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
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35
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Zhou X, Wu Y, Song Y, Wang B, Cai Y, Miao C. Mechanistic and therapeutic insights into the function of N6-methyladenosine in arthritic diseases. Inflamm Res 2025; 74:7. [PMID: 39762508 DOI: 10.1007/s00011-024-01969-3] [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: 06/04/2024] [Revised: 10/22/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
OBJECTIVE Arthritis is a class of diseases, characterized by joint and surrounding inflammation, accompanied by joint swelling, pain, dysfunction. According to different factors, arthritis can be divided into osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and so on. N6-methyladenosine (m6A) is the most common internal modification of eukaryotic mRNA and is involved in splicing, stabilization, output and degradation of RNA metabolism. This review systematically summarized current insights into the mechanism of m6A in arthritis. METHODS The studies related to the involvement of m6A in the pathogenesis of arthritis reported in PubMed, Google scholar, and other open source literatures were investigated to evaluate the important roles of m6A in arhtritis, and the clinical relevances. RESULTS AND CONCLUSIONS M6A methylation regulators play the roles of writers, erasers, and readers, are crucial for regulating gene expression, and play important roles in many biological processes such as virus replication and cell differentiation. In addition, more and more studies have shown that m6A is closely related to the development of arthritis. As a new therapeutic target for arthritis, m6A has a wide influence on the pathological mechanism of arthritis. However, further research is needed to determine how m6A affects arthritis pathology and its use in target therapy and diagnosis.
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Affiliation(s)
- Xinyue Zhou
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350 Longzihu Road, Xinzhan District, Hefei, 230012, Anhui, China
| | - Yajie Wu
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350 Longzihu Road, Xinzhan District, Hefei, 230012, Anhui, China
| | - Yingqiu Song
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350 Longzihu Road, Xinzhan District, Hefei, 230012, Anhui, China
| | - Bing Wang
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350 Longzihu Road, Xinzhan District, Hefei, 230012, Anhui, China
| | - Yikang Cai
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350 Longzihu Road, Xinzhan District, Hefei, 230012, Anhui, China
| | - Chenggui Miao
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350 Longzihu Road, Xinzhan District, Hefei, 230012, Anhui, China.
- Institute of Prevention and Treatment of Rheumatoid Arthritis, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China.
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China.
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, Hong Kong SAR, China.
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36
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Hu T, Wang G, Wang D, Deng Y, Wang W. m6A methylation modification: Potential pathways to suppress osteosarcoma metastasis. Int Immunopharmacol 2025; 145:113759. [PMID: 39662272 DOI: 10.1016/j.intimp.2024.113759] [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: 09/09/2024] [Revised: 11/16/2024] [Accepted: 11/28/2024] [Indexed: 12/13/2024]
Abstract
Osteosarcoma is a highly aggressive malignant bone tumor prone to metastasis, and its metastatic process is one of the main reasons for treatment failure and poor prognosis. Recent studies have demonstrated that modification of m6A methylation plays an important role in osteosarcoma metastasis, influencing both invasion and metastasis through various signaling pathways. Therefore, clarification of the specific effects of m6A methylation modification in osteosarcoma may reveal ways to improve the prognosis of osteosarcoma patients. The roles of various components involved in the m6A methylation modification process in osteosarcoma have been investigated, with studies focusing more on their effects than on their mechanisms. In this review, we focus on the interactions between the "writers," "erasers," and "readers" of m6A methylation and tumor metastasis-related factors to enhance the understanding of osteosarcoma and m6A methylation modification, with the aim of identifying clinical diagnostic biomarkers and potential therapeutic targets for osteosarcoma metastasis.
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Affiliation(s)
- Tianrui Hu
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Guowei Wang
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Dong Wang
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Youwen Deng
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
| | - Weiguo Wang
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
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37
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Su N, Yu X, Duan M, Shi N. Recent advances in methylation modifications of microRNA. Genes Dis 2025; 12:101201. [PMID: 39524539 PMCID: PMC11550756 DOI: 10.1016/j.gendis.2023.101201] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/13/2023] [Accepted: 11/19/2023] [Indexed: 11/16/2024] Open
Abstract
microRNAs (miRNAs) are short single-stranded non-coding RNAs between 21 and 25 nt in length in eukaryotic organisms, which control post-transcriptional gene expression. Through complementary base pairing, miRNAs generally bind to their target messenger RNAs and repress protein production by destabilizing the messenger RNA and translational silencing. They regulate almost all life activities, such as cell proliferation, differentiation, apoptosis, tumorigenesis, and host-pathogen interactions. Methylation modification is the most common RNA modification in eukaryotes. miRNA methylation exists in different types, mainly N6-methyladenosine, 5-methylcytosine, and 7-methylguanine, which can change the expression level and biological mode of action of miRNAs and improve the activity of regulating gene expression in a very fine-tuned way with flexibility. In this review, we will summarize the recent findings concerning methylation modifications of miRNA, focusing on their biogenesis and the potential role of miRNA fate and functions.
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Affiliation(s)
| | | | | | - Ning Shi
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, China
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38
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Jiang J, Zhang Y, Wang J, Qin Y, Zhao C, He K, Wang C, Liu Y, Feng H, Cai H, He S, Li R, Galstyan DS, Yang L, Lim LW, de Abreu MS, Kalueff AV. Using Zebrafish Models to Study Epitranscriptomic Regulation of CNS Functions. J Neurochem 2025; 169:e16311. [PMID: 39825734 DOI: 10.1111/jnc.16311] [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: 10/11/2024] [Revised: 12/18/2024] [Accepted: 12/30/2024] [Indexed: 01/20/2025]
Abstract
Epitranscriptomic regulation of cell functions involves multiple post-transcriptional chemical modifications of coding and non-coding RNA that are increasingly recognized in studying human brain disorders. Although rodent models are presently widely used in neuroepitranscriptomic research, the zebrafish (Danio rerio) has emerged as a useful and promising alternative model species. Mounting evidence supports the importance of RNA modifications in zebrafish CNS function, providing additional insights into epitranscriptomic mechanisms underlying a wide range of brain disorders. Here, we discuss recent data on the role of RNA modifications in CNS regulation, with a particular focus on zebrafish models, as well as evaluate current problems, challenges, and future directions of research in this field of molecular neurochemistry.
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Affiliation(s)
- Jiayou Jiang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Yunqian Zhang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Jiyi Wang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Yixin Qin
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Chonguang Zhao
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Kai He
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Chaoming Wang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Yucheng Liu
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Haoyu Feng
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Huiling Cai
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Shulei He
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Ruiyu Li
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - David S Galstyan
- Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Longen Yang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Lee Wei Lim
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Murilo S de Abreu
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
- Moscow Institute of Physics and Technology, Moscow, Russia
- Western Caspian University, Baku, Azerbaijan
| | - Allan V Kalueff
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Moscow Institute of Physics and Technology, Moscow, Russia
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39
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Wu Q, Ito M, Fujii T, Tanaka K, Nakatani K, Izumi Y, Bamba T, Baba T, Maehara K, Tomimatsu K, Takemoto T, Ohkawa Y, Harada A. Defects in the H3t Gene Cause an Increase in Leydig Cells With Impaired Spermatogenesis in Mice. Genes Cells 2025; 30:e13182. [PMID: 39624989 DOI: 10.1111/gtc.13182] [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: 08/19/2024] [Revised: 10/08/2024] [Accepted: 10/08/2024] [Indexed: 12/20/2024]
Abstract
Abnormalities in spermatogenesis, a fundamental component of male reproductive function, can cause male infertility. Somatic cells constituting the testis microenvironment are essential for controlling normal spermatogenesis. Although testicular somatic cells are thought to sense and respond to germ cells to ensure proper spermatogenesis, the details of this signaling mechanism are unknown. Here, we investigated somatic cell dynamics in testicular tissue lacking spermatogenesis using the mice with deletion of the testis-specific histone H3 variant gene H3t. Testicular tissue sections of H3tΔ/Δ mice exhibited an increased interstitial area compared with those of wild-type mice, which was primarily attributed to an increase in Leydig cell numbers. Furthermore, this increase in Leydig cells led to increased testosterone synthesis, which occurred alongside cellular senescence-associated β-galactosidase activity. These findings suggest that Leydig cells monitor the progress of spermatogenesis and possess a mechanism to promote functional germ cell formation.
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Affiliation(s)
- Qianmei Wu
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Miho Ito
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Takeru Fujii
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Kaori Tanaka
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Kohta Nakatani
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Izumi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Takeshi Bamba
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Takashi Baba
- Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazumitsu Maehara
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Kosuke Tomimatsu
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Tatsuya Takemoto
- Laboratory for Embryology, Institute for Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Yasuyuki Ohkawa
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Akihito Harada
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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40
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Wang Y, Pang Z, He W, Ren P, He Q, Jin J. LncRNA HOXB3OS improves high glucose-mediated podocyte damage and progression of diabetic kidney disease through enhancing SIRT1 mRNA stability. Biomed Pharmacother 2025; 182:117770. [PMID: 39693905 DOI: 10.1016/j.biopha.2024.117770] [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: 08/06/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024] Open
Abstract
High glucose (HG)-mediated podocyte damage can be ameliorated by lncRNA HOXB3OS, and exosomes derived from adipose-derived mesenchymal stem cells (ADSCs-Exo) can ameliorate the progression of diabetic kidney disease (DKD) dependening on RNA. To investigate the mechanism by which HOXB3OS improves podocyte injury and the effects of engineered ADSCs-Exo with a high abundance of HOXB3OS on DKD progression, MPC5 cells stimulated with HG and db/db mice were used to develop a podocyte injury model and type II DKD mouse model, respectively. HOXB3OS expression and mRNA level of SIRT1 were detected by qRT-PCR. The protein content of SIRT1 and Ythdc2 was measured through WB, IHC, and IF assays. CCK-8 assay and flow cytometry assay were used to detect cell viability and apoptosis rate of MPC5 cells. RIP assay was used to investigate the binding capacity of Ythdc2 to HOXB3OS or SIRT1 mRNA. Albuminuria, renal function and glomerular structure were observed by kits and PAS, respectively. Consequently, we found that HOXB3OS combined with Ythdc2 and inhibited the binding of Ythdc2 to SIRT1 mRNA, hence inhibiting SIRT1 mRNA degradation. SIRT1 siRNA inhibited the effect of Ythdc2 siRNA on HOXB3OS knock-down or HG-induced podocyte injury. ADSCs-Exo with a high content of HOXB3OS ameliorated HG-mediated podocyte damage and DKD progression. This suggests that engineered ADSCs-Exo with HOXB3OS can suppress Ythdc2-mediated SIRT1 mRNA degradation by disturbing the binding of Ythdc2 to SIRT1 mRNA as well as reverse SIRT1 down-regulation induced by HG, thereby ameliorating podocyte injury and DKD progression.
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Affiliation(s)
- Yifei Wang
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Zhengyi Pang
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Wenfang He
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Peiyao Ren
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China
| | - Qiang He
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China.
| | - Juan Jin
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China; Provincial Key Laboratory for Research and Translation on the Syndrome of Kidney Deficiency Accompanied by Blood Stasis and Turbidity, China.
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Rupareliya M, Shende P. Influence of RNA Methylation on Cancerous Cells: A Prospective Approach for Alteration of In Vivo Cellular Composition. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:79-103. [PMID: 39259424 DOI: 10.1007/5584_2024_820] [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: 09/13/2024]
Abstract
RNA methylation is a dynamic and ubiquitous post-transcriptional modification that plays a pivotal role in regulating gene expression in various conditions like cancer, neurological disorders, cardiovascular diseases, viral infections, metabolic disorders, and autoimmune diseases. RNA methylation manifests across diverse RNA species including messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA), exerting pivotal roles in gene expression regulation and various biological phenomena. Aberrant activity of writer, eraser, and reader proteins enables dysregulated methylation landscape across diverse malignancy transcriptomes, frequently promoting cancer pathogenesis. Numerous oncogenic drivers, tumour suppressors, invasion/metastasis factors, and signalling cascade components undergo methylation changes that modulate respective mRNA stability, translation, splicing, transport, and protein-RNA interactions accordingly. Functional studies confirm methylation-dependent alterations drive proliferation, survival, motility, angiogenesis, stemness, metabolism, and therapeutic evasion programs systemically. Methyltransferase overexpression typifies certain breast, liver, gastric, and other carcinomas correlating with adverse clinical outcomes like diminished overall survival. Mapping efforts uncover nodal transcripts for targeted drug development against hyperactivated regulators including METTL3. Some erasers and readers also suitable lead candidates based on apparent synthetic lethality. Proteomic screens additionally highlight relevant methylation-sensitive effector pathways amenable to combinatorial blockade, reversing compensatory signalling mechanisms that facilitate solid tumour progression. Quantifying global methylation burdens and responsible enzymes clinically predicts patient prognosis, risk stratification for adjuvant therapy, and overall therapeutic responsiveness.
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Affiliation(s)
- Manali Rupareliya
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, Mumbai, India
| | - Pravin Shende
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, Mumbai, India.
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Tian S, Song Y, Guo L, Zhao H, Bai M, Miao M. Epigenetic Mechanisms in Osteoporosis: Exploring the Power of m 6A RNA Modification. J Cell Mol Med 2025; 29:e70344. [PMID: 39779466 PMCID: PMC11710941 DOI: 10.1111/jcmm.70344] [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: 09/05/2024] [Revised: 12/12/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Osteoporosis, recognised as a metabolic disorder, has emerged as a significant burden on global health. Although available treatments have made considerable advancements, they remain inadequately addressed. In recent years, the role of epigenetic mechanisms in skeletal disorders has garnered substantial attention, particularly concerning m6A RNA modification. m6A is the most prevalent dynamic and reversible modification in eukaryotes, mediating various metabolic processes of mRNAs, including splicing, structural conversion, translation, translocation and degradation and serves as a crucial component of epigenetic modification. Research has increasingly validated that m6A plays a vital role in the proliferation, differentiation, migration, invasion,and repair of bone marrow mesenchymal stem cells (BMSCs), osteoblasts and osteoclasts, all of which impact the whole process of osteoporosis pathogenesis. Continuous efforts have been made to target m6A regulators and natural products derived from traditional medicine, which exhibit multiple biological activities such as anti-inflammatory and anticancer effects, have emerged as a valuable resources for m6A drug discovery. This paper elaborates on m6A methylation and its regulatory role in osteoporosis, emphasising its implications for diagnosis and treatment, thereby providing theoretical references.
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Affiliation(s)
- Shuo Tian
- Academy of Traditional Chinese MedicineHenan University of Chinese MedicineZhengzhouChina
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu‐YaoZhengzhouChina
| | - Yagang Song
- Academy of Traditional Chinese MedicineHenan University of Chinese MedicineZhengzhouChina
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu‐YaoZhengzhouChina
| | - Lin Guo
- School of PharmacyHenan University of Chinese MedicineZhengzhouChina
| | - Hui Zhao
- Academy of Traditional Chinese MedicineHenan University of Chinese MedicineZhengzhouChina
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu‐YaoZhengzhouChina
| | - Ming Bai
- Academy of Traditional Chinese MedicineHenan University of Chinese MedicineZhengzhouChina
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu‐YaoZhengzhouChina
| | - Mingsan Miao
- Academy of Traditional Chinese MedicineHenan University of Chinese MedicineZhengzhouChina
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu‐YaoZhengzhouChina
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Qadri SW, Shah NM, Muddashetty RS. Epitranscriptome-Mediated Regulation of Neuronal Translation. WILEY INTERDISCIPLINARY REVIEWS. RNA 2025; 16:e70004. [PMID: 39963903 DOI: 10.1002/wrna.70004] [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: 03/09/2024] [Revised: 12/02/2024] [Accepted: 01/24/2025] [Indexed: 04/10/2025]
Abstract
Epitranscriptomic modification of RNA is an important layer of regulation for gene expression. RNA modifications come in many flavors and generate a complex tapestry of a regulatory network. Here, we focus on two major RNA modifications, one on rRNA (2'O Methylation) and another on mRNA (N6-Methyladenosine [m6A]) and their impact on translation. The 2'O methyl group addition on the ribose sugar of rRNA plays a critical role in RNA folding, ribosome assembly, and its interaction with many RNA binding proteins. Differential methylation of these sites contributes to ribosome heterogeneity and generates potential "specialized ribosomes." Specialized ribosomes are proposed to play a variety of important roles in maintaining pluripotency, lineage specification, and compartmentalized and activity-mediated translation in neurons. The m6A modification, on the other hand, determines the stability, transport, and translation of subclasses of mRNA. The dynamic nature of m6A owing to the localization and activity of its writers, readers, and erasers makes it a powerful tool for spatiotemporal regulation of translation. While substantial information has accumulated on the nature and abundance of these modifications, their functional consequences are still understudied. In this article, we review the literature constructing the body of our understanding of these two modifications and their outcome on the regulation of translation in general and their impact on the nervous system in particular. We also explore the possibility of how these modifications may collaborate in modulating translation and provoke the thought to integrate the functions of multiple epitranscriptome modifications.
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Affiliation(s)
- Syed Wasifa Qadri
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Nisa Manzoor Shah
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Ravi S Muddashetty
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
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Wang YY, Ye LH, Zhao AQ, Gao WR, Dai N, Yin Y, Zhang X. M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells. Cancer Biol Ther 2024; 25:2306674. [PMID: 38372700 PMCID: PMC10878024 DOI: 10.1080/15384047.2024.2306674] [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: 10/22/2023] [Accepted: 01/14/2024] [Indexed: 02/20/2024] Open
Abstract
DIRAS family GTPase 1 (DIRAS1) has been reported as a potential tumor suppressor in other human cancer. However, its expression pattern and role in cervical cancer remain unknown. Knockdown of DIRAS1 significantly promoted the proliferation, growth, migration, and invasion of C33A and SiHa cells cultured in vitro. Overexpression of DIRAS1 significantly inhibited the viability and motility of C33A and SiHa cells. Compared with normal cervical tissues, DIRAS1 mRNA levels were significantly lower in cervical cancer tissues. DIRAS1 protein expression was also significantly reduced in cervical cancer tissues compared with para-cancerous tissues. In addition, DIRAS1 expression level in tumor tissues was significantly negatively correlated with the pathological grades of cervical cancer patients. DNA methylation inhibitor (5-Azacytidine) and histone deacetylation inhibitor (SAHA) resulted in a significant increase in DIRAS1 mRNA levels in C33A and SiHa cells, but did not affect DIRAS1 protein levels. FTO inhibitor (FB23-2) significantly down-regulated intracellular DIRAS1 mRNA levels, but significantly up-regulated DIRAS1 protein levels. Moreover, the down-regulation of METTL3 and METTL14 expression significantly inhibited DIRAS1 protein expression, whereas the down-regulation of FTO and ALKBH5 expression significantly increased DIRAS1 protein expression. In conclusion, DIRAS1 exerts a significant anti-oncogenic function and its expression is significantly downregulated in cervical cancer cells. The m6A modification may be a key mechanism to regulate DIRAS1 mRNA stability and protein translation efficiency in cervical cancer.
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Affiliation(s)
- Yu-Yan Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Lian-Hua Ye
- Department of Internal Medicine, Zigong Fourth People’s Hospital, Zigong, Sichuan, China
| | - An-Qi Zhao
- Department of Obstetrics and Gynecology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Wei-Ran Gao
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Ning Dai
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Yu Yin
- Operating Rooms, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Xin Zhang
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
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45
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Sun Y, Wu J, Sun W, Liu C, Shi X. Novel insights into the interaction between IGF2BPs and ncRNAs in cancers. Cancer Cell Int 2024; 24:437. [PMID: 39732659 DOI: 10.1186/s12935-024-03591-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: 08/16/2024] [Accepted: 11/28/2024] [Indexed: 12/30/2024] Open
Abstract
Insulin-like growth factor II mRNA-binding proteins (IGF2BPs), a family of RNA-binding proteins, are pivotal in regulating RNA dynamics, encompassing processes such as localization, metabolism, stability, and translation through the formation of ribonucleoprotein complexes. First identified in 1999 for their affinity to insulin-like growth factor II mRNA, IGF2BPs have been implicated in promoting tumor malignancy behaviors, including proliferation, metastasis, and the maintenance of stemness, which are associated with unfavorable outcomes in various cancers. Additionally, non-coding RNAs (ncRNAs), particularly long non-coding RNAs, circular RNAs, and microRNAs, play critical roles in cancer progression through intricate protein-RNA interactions. Recent studies, predominantly from 2018 onward, indicate that IGF2BPs can recognize and modulate ncRNAs via N6-methyladenosine (m6A) modifications, enriching the regulatory landscape of RNA-protein interactions in the context of cancer. This review explores the latest insights into the interplay between IGF2BPs and ncRNAs, emphasizing their potential influence on cancer biology.
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Affiliation(s)
- Yaya Sun
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Junjie Wu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Weimin Sun
- Department of General Surgery, Xuyi People's Hospital, Huai'an, 211700, China.
| | - Congxing Liu
- Department of General Surgery, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
| | - Xin Shi
- Department of General Surgery, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
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Uddin MB, Wang Z, Yang C. Epitranscriptomic RNA m 6A Modification in Cancer Therapy Resistance: Challenges and Unrealized Opportunities. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 12:e2403936. [PMID: 39661414 PMCID: PMC11775542 DOI: 10.1002/advs.202403936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/24/2024] [Indexed: 12/12/2024]
Abstract
Significant advances in the development of new cancer therapies have given rise to multiple novel therapeutic options in chemotherapy, radiotherapy, immunotherapy, and targeted therapies. Although the development of resistance is often reported along with temporary disease remission, there is often tumor recurrence of an even more aggressive nature. Resistance to currently available anticancer drugs results in poor overall and disease-free survival rates for cancer patients. There are multiple mechanisms through which tumor cells develop resistance to therapeutic agents. To date, efforts to overcome resistance have only achieved limited success. Epitranscriptomics, especially related to m6A RNA modification dysregulation in cancer, is an emerging mechanism for cancer therapy resistance. Here, recent studies regarding the contributions of m6A modification and its regulatory proteins to the development of resistance to different cancer therapies are comprehensively reviewed. The promise and potential limitations of targeting these entities to overcome resistance to various anticancer therapies are also discussed.
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Affiliation(s)
- Mohammad Burhan Uddin
- Department of Pharmaceutical SciencesNorth South UniversityBashundharaDhaka1229Bangladesh
| | - Zhishan Wang
- Stony Brook Cancer CenterStony Brook UniversityStony BrookNY11794USA
| | - Chengfeng Yang
- Stony Brook Cancer CenterStony Brook UniversityStony BrookNY11794USA
- Department of PathologyRenaissance School of MedicineStony Brook UniversityStony BrookNY11794USA
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Huart C, Gupta MS, Van Ginderachter JA. The role of RNA modifications in disease-associated macrophages. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102315. [PMID: 39296330 PMCID: PMC11408368 DOI: 10.1016/j.omtn.2024.102315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
In recent years, the field of epitranscriptomics has witnessed significant breakthroughs with the identification of more than 150 different chemical modifications in different RNA species. It has become increasingly clear that these chemical modifications play an important role in the regulation of fundamental processes linked to cell fate and development. Further interest was sparked by the ability of the epitranscriptome to regulate pathogenesis. However, despite the involvement of macrophages in a multitude of diseases, a clear knowledge gap exists in the understanding of how RNA modifications regulate the phenotype of these cells. Here, we provide a comprehensive overview of the known roles of macrophage RNA modifications in the context of different diseases.
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Affiliation(s)
- Camille Huart
- Lab of Cellular and Molecular Immunology, Brussels Center for Immunology (BCIM), Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Mayuk Saibal Gupta
- Lab of Cellular and Molecular Immunology, Brussels Center for Immunology (BCIM), Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Jo A Van Ginderachter
- Lab of Cellular and Molecular Immunology, Brussels Center for Immunology (BCIM), Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
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Zhou L, Li R, Wang F, Zhou R, Xia Y, Jiang X, Cheng S, Wang F, Li D, Zhang J, Mao L, Cai X, Zhang H, Qiu J, Tian X, Zou Z, Chen C. N6-methyladenosine demethylase FTO regulates neuronal oxidative stress via YTHDC1-ATF3 axis in arsenic-induced cognitive dysfunction. JOURNAL OF HAZARDOUS MATERIALS 2024; 480:135736. [PMID: 39265400 DOI: 10.1016/j.jhazmat.2024.135736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/25/2024] [Accepted: 09/01/2024] [Indexed: 09/14/2024]
Abstract
Excessive exposure to metals in daily life has been proposed as an environmental risk factor for neurological disorders. Oxidative stress is an inevitable stage involved in the neurotoxic effects induced by metals, nevertheless, the underlying mechanisms are still unclear. In this study, we used arsenic as a representative environmental heavy metal to induce neuronal oxidative stress and demonstrated that both in vitro and in vivo exposure to arsenic significantly increased the level of N6-methyladenosine (m6A) by down-regulating its demethylase FTO. Importantly, the results obtained from FTO transgenic mice and FTO overexpressed/knockout cells indicated that FTO likely regulated neuronal oxidative stress by modulating activating transcription factor 3 (ATF3) in a m6A-dependent manner. We also identified the specific m6A reader protein, YTHDC1, which interacted with ATF3 and thereby affecting its regulatory effects on oxidative stress. To further explore potential intervention strategies, cerebral metabolomics was conducted and we newly identified myo-inositol as a metabolite that exhibited potential in protecting against arsenic-induced oxidative stress and cognitive dysfunction. Overall, these findings provide new insights into the importance of the FTO-ATF3 signaling axis in neuronal oxidative stress from an m6A perspective, and highlight a beneficial metabolite that can counteract the oxidative stress induced by arsenic.
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Affiliation(s)
- Lixiao Zhou
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Renjie Li
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Fu Wang
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Ruiqi Zhou
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Yinyin Xia
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Xuejun Jiang
- Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China
| | - Shuqun Cheng
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Fanghong Wang
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Danyang Li
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Jun Zhang
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China
| | - Lejiao Mao
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xuemei Cai
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Hongyang Zhang
- Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China; Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Jingfu Qiu
- Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China; Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing 400016, China
| | - Xin Tian
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Zhen Zou
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China.
| | - Chengzhi Chen
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China.
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Qin L, Zeng X, Qiu X, Chen X, Liu S. The role of N6-methyladenosine modification in tumor angiogenesis. Front Oncol 2024; 14:1467850. [PMID: 39691597 PMCID: PMC11649548 DOI: 10.3389/fonc.2024.1467850] [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: 07/21/2024] [Accepted: 11/11/2024] [Indexed: 12/19/2024] Open
Abstract
Tumor angiogenesis is a characteristics of malignant cancer progression that facilitates cancer cell growth, diffusion and metastasis, and has an indispensable role in cancer development. N6-methyladenosine (m6A) is among the most prevalent internal modifications in eukaryotic RNAs, and has considerable influence on RNA metabolism, including its transcription, splicing, localization, translation, recognition, and degradation. The m6A modification is generated by m6A methyltransferases ("writers"), removed by m6A demethylases ("erasers"), and recognized by m6A-binding proteins ("readers"). There is accumulating evidence that abnormal m6A modification is involved in the pathogenesis of multiple diseases, including cancers, and promotes cancer occurrence, development, and progression through its considerable impact on oncoprotein expression. Furthermore, increasing studies have demonstrated that m6A modification can influence angiogenesis in cancers through multiple pathways to regulate malignant processes. In this review, we elaborate the role of m6A modification in tumor angiogenesis-related molecules and pathways in detail, providing insights into the interactions between m6A and tumor angiogenesis. Moreover, we describe how targeting m6A modification in combination with anti-angiogenesis drugs is expected to be a promising anti-tumor treatment strategy, with potential value for addressing the challenge of drug resistance.
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Affiliation(s)
| | | | | | | | - Shiquan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical
University, Nanning, Guangxi, China
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50
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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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