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1
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Atri Y, Bharti H, Sahani N, Sarkar DP, Nag A. CUL4A silencing attenuates cervical carcinogenesis and improves Cisplatin sensitivity. Mol Cell Biochem 2024; 479:1041-1058. [PMID: 37285039 DOI: 10.1007/s11010-023-04776-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 05/21/2023] [Indexed: 06/08/2023]
Abstract
CUL4A is an ubiquitin ligase deregulated in numerous pathologies including cancer and even hijacked by viruses for facilitating their survival and propagation. However, its role in Human papilloma virus (HPV)-mediated cervical carcinogenesis remains elusive. The UALCAN and GEPIA datasets were analyzed to ascertain the transcript levels of CUL4A in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients. Subsequently, various biochemical assays were employed to explore the functional contribution of CUL4A in cervical carcinogenesis and to shed some light on its involvement in Cisplatin resistance in cervical cancer. Our UALCAN and GEPIA datasets analyses reveal elevated CUL4A transcript levels in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients that correlate with adverse clinicopathological parameters such as tumor stage and lymph node metastasis. Kaplan-Meier plot and GEPIA assessment depict poor prognosis of CESC patients having high CUL4A expression. Varied biochemical assays illustrate that CUL4A inhibition severely curtails hallmark malignant properties such as cellular proliferation, migration, and invasion of cervical cancer cells. We also show that CUL4A knockdown in HeLa cells causes increased susceptibility and better apoptotic induction toward Cisplatin, a mainstay drug used in cervical cancer treatment. More interestingly, we find reversion of Cisplatin-resistant phenotype of HeLa cells and an augmented cytotoxicity towards the platinum compound upon CUL4A downregulation. Taken together, our study underscores CUL4A as a cervical cancer oncogene and illustrates its potential as a prognosis indicator. Our investigation provides a novel avenue in improving current anti-cervical cancer therapy and overcoming the bottle-neck of Cisplatin resistance.
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Affiliation(s)
- Yama Atri
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Hina Bharti
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Nandini Sahani
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Debi P Sarkar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Alo Nag
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India.
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2
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Tavlas P, Nikou S, Geramoutsou C, Bosgana P, Tsaniras SC, Melachrinou M, Maroulis I, Bravou V. CUL4A Ubiquitin Ligase Is an Independent Predictor of Overall Survival in Pancreatic Adenocarcinoma. Cancer Genomics Proteomics 2024; 21:166-177. [PMID: 38423594 PMCID: PMC10905276 DOI: 10.21873/cgp.20438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/22/2024] [Accepted: 02/06/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND/AIM Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Genomic instability due to defects in cell-cycle regulation/mitosis or deficient DNA-damage repair is a major driver of PDAC progression with clinical relevance. Deregulation of licensing of DNA replication leads to DNA damage and genomic instability, predisposing cells to malignant transformation. While overexpression of DNA replication-licensing factors has been reported in several human cancer types, their role in PDAC remains largely unknown. We aimed here to examine the expression and prognostic significance of the DNA replication-licensing factors chromatin licensing and DNA replication factor 1 (CDT1), cell-division cycle 6 (CDC6), minichromosome maintenance complex component 7 (MCM7) and also of the ubiquitin ligase regulator of CDT1, cullin 4A (CUL4A), in PDAC. MATERIALS AND METHODS Expression levels of CUL4, CDT1, CDC6 and MCM7 were evaluated by immunohistochemistry in 76 formalin-fixed paraffin-embedded specimens of PDAC patients in relation to DNA-damage response marker H2AX, clinicopathological parameters and survival. We also conducted bioinformatics analysis of data from online available databases to corroborate our findings. RESULTS CUL4A and DNA replication-licensing factors were overexpressed in patients with PDAC and expression of CDT1 positively correlated with H2AX. Expression of CUL4A and CDT1 positively correlated with lymph node metastasis. Importantly, elevated CUL4A expression was associated with reduced overall survival and was an independent indicator of poor prognosis on multivariate analysis. CONCLUSION Our findings implicate CUL4A, CDT1, CDC6 and MCM7 in PDAC progression and identify CUL4A as an independent prognostic factor for this disease.
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Affiliation(s)
- Panagiotis Tavlas
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece
- Department of Surgery, University General Hospital of Patras, Patras, Greece
| | - Sofia Nikou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece
| | - Christina Geramoutsou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece
| | - Pinelopi Bosgana
- Department of Pathology, School of Medicine, University of Patras, Patras, Greece
| | - Spyridon Champeris Tsaniras
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, U.S.A
- International Institute of Anticancer Research, Kapandriti, Greece
| | - Maria Melachrinou
- Department of Pathology, School of Medicine, University of Patras, Patras, Greece
| | - Ioannis Maroulis
- Department of Surgery, University General Hospital of Patras, Patras, Greece
| | - Vasiliki Bravou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece;
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Yang Z, Jia Y, Wang S, Zhang Y, Fan W, Wang X, He L, Shen X, Yang X, Zhang Y, Yang H. Retinoblastoma-Binding Protein 5 Regulates H3K4 Methylation Modification to Inhibit the Proliferation of Melanoma Cells by Inactivating the Wnt/ β-Catenin and Epithelial-Mesenchymal Transition Pathways. JOURNAL OF ONCOLOGY 2023; 2023:5093941. [PMID: 36866240 PMCID: PMC9974310 DOI: 10.1155/2023/5093941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/29/2022] [Accepted: 01/20/2023] [Indexed: 02/25/2023]
Abstract
Histone 3 lysine 4 methylation (H3K4me), especially histone 3 lysine 4 trimethylation (H3K4me3), is one of the most extensively studied patterns of histone modification and plays crucial roles in many biological processes. However, as a part of H3K4 methyltransferase that participates in H3K4 methylation and transcriptional regulation, retinoblastoma-binding protein 5 (RBBP5) has not been well studied in melanoma. The present study sought to explore RBBP5-mediated H3K4 histone modification and the potential mechanisms in melanoma. RBBP5 expression in melanoma and nevi specimens was detected by immunohistochemistry. Western blotting was performed for three pairs of melanoma cancer tissues and nevi tissues. In vitro and in vivo assays were used to investigate the function of RBBP5. The molecular mechanism was determined using RT-qPCR, western blotting, ChIP assays, and Co-IP assays. Our study showed that RBBP5 was significantly downregulated in melanoma tissue and cells compared with nevi tissues and normal epithelia cells (P < 0.05). Reducing RBBP5 in human melanoma cells leads to H3K4me3 downregulation and promotes cell proliferation, migration, and invasion. On the one hand, we verified that WSB2 was an upstream gene of RBBP5-mediated H3K4 modification, which could directly bind to RBBP5 and negatively regulate its expression. On the other hand, we also confirmed that p16 (a cancer suppressor gene) was a downstream target of H3K4me3, the promoter of which can directly bind to H3K4me3. Mechanistically, our data revealed that RBBP5 inactivated the Wnt/β-catenin and epithelial-mesenchymal transition (EMT) pathways (P < 0.05), leading to melanoma suppression. Histone methylation is rising as an important factor affecting tumorigenicity and tumor progression. Our findings verified the significance of RBBP5-mediated H3K4 modification in melanoma and the potential regulatory mechanisms of melanoma proliferation and growth, suggesting that RBBP5 is a potential therapeutic target for the treatment of melanoma.
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Affiliation(s)
- Zhiqin Yang
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
- 2Departments of Gynecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Yue Jia
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Shaojia Wang
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Yongjun Zhang
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Wen Fan
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
- 3Departments of Reproduction, The Second Affiliated Hospital of Kunming Medical University, Kunming 650106, China
| | - Xin Wang
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Liang He
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Xiaoyu Shen
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Xiangqun Yang
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Yi Zhang
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Hongying Yang
- 1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
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4
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Li X, Han YR, Xuefeng X, Ma YX, Xing GS, Yang ZW, Zhang Z, Shi L, Wu XL. Lentivirus-mediated short hairpin RNA interference of CENPK inhibits growth of colorectal cancer cells with overexpression of Cullin 4A. World J Gastroenterol 2022; 28:5420-5443. [PMID: 36312839 PMCID: PMC9611705 DOI: 10.3748/wjg.v28.i37.5420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/24/2022] [Accepted: 09/12/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. The identification of novel diagnostic and prognostic biomarkers for CRC is a key research imperative. Immunohistochemical analysis has revealed high expression of centromere protein K (CENPK) in CRC. However, the role of CENPK in the progression of CRC is not well characterized. AIM To evaluate the effects of knockdown of CENPK and overexpression of Cullin 4A (CUL4A) in RKO and HCT116 cells. METHODS Human colon cancer samples were collected and tested using a human gene expression chip. We identified CENPK as a potential oncogene for CRC based on bioinformatics analysis. In vitro experiments verified the function of this gene. We investigated the expression of CENPK in RKO and HCT116 cells using quantitative polymerase chain reaction (qPCR), western blot, and flow cytometry. The effect of short hairpin RNA (shRNA) virus-infected RKO cells on tumor growth was evaluated in vivo using quantitative analysis of fluorescence imaging. To evaluate the effects of knockdown of CENPK and overexpression of CUL4A in RKO and HCT116 cells, we performed a series of in vitro experiments, using qPCR, western blot, MTT assay, and flow cytometry. RESULTS We demonstrated overexpression of CENPK in human colon cancer samples. CENPK was an independent risk factor in patients with CRC. The downstream genes FBX32, CUL4A, and Yes-associated protein isoform 1 were examined to evaluate the regulatory action of CENPK in RKO cells. Significantly delayed xenograft tumor emergence, slower growth rate, and lower final tumor weight and volume were observed in the CENPK short hairpin RNA virus infected group compared with the CENPK negative control group. The CENPK gene interference inhibited the proliferation of RKO cells in vitro and in vivo. The lentivirus-mediated shRNA interference of CENPK inhibited the proliferation of RKO and HCT116 colon cancer cells, with overexpression of the CUL4A. CONCLUSION We indicated a potential role of CENPK in promoting tumor proliferation, and it may be a novel diagnostic and prognostic biomarker for CRC.
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Affiliation(s)
- Xian Li
- Clinical Medical Research Center, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Yi-Ru Han
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Xuefeng Xuefeng
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Yong-Xiang Ma
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Guo-Sheng Xing
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Zhi-Wen Yang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Zhen Zhang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Lin Shi
- Department of Pathology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Xin-Lin Wu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
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5
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Zhao J, Duan Q, Dong C, Cui J. Cul4a attenuates LPS-induced acute kidney injury via blocking NF-kB signaling pathway in sepsis. J Med Biochem 2022; 41:62-70. [PMID: 35611245 PMCID: PMC9069243 DOI: 10.5937/jomb0-33096] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 07/29/2021] [Indexed: 11/24/2022] Open
Abstract
Background Acute kidney injury (AKI) is a common disease that can develop into end-stage kidney disease. Sepsis is one of the main causes of AKI. Currently, there is no satisfactory way to treat septic AKI. Therefore, we have shown the protective function of Cul4a in septic AKI and its molecular mechanism. Methods The cellular and animal models of septic AKI were established by using lipopolysaccharide (LPS). Western blot (WB) was employed to analyze Cul4a expression. RT-qPCR was employed to test the expression of Cul4a, SOD1, SOD2, GPX1, CAT, IL-6, TNF-a, Bcl-2, IL1b, Bax and KIM-1 mRNA. ELISA was performed to detect the contents of inflammatory factors and LDH. CCK-8 was utilized to detect cell viability. Flow cytometry was utilized to analyze the apoptosis. DHE-ROS kit was used to detect the content of ROS. Results Cul4a was down-regulated in cellular and animal models of septic AKI. Oxidative stress is obviously induced by LPS, as well as apoptosis and inflammation. However, these can be significantly inhibited by up-regulating Cul4a. Moreover, LPS induced the activation of the NF-kB pathway, which could also be inhibited by overexpression of Cul4a. Conclusions Cul4awas found to be a protective factor in septic AKI, which could inhibit LPS-induced oxidative stress, apoptosis and inflammation of HK-2 cells by inhibiting the NF-kB pathway.
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Affiliation(s)
- Jing Zhao
- Yantaishan Hospital, Department of Critical Care Medicine, Yantai, China
| | - Qiuxia Duan
- The Third People's Hospital of Qingdao, Department of Critical Care Medicine, Qingdao, China
| | - Cuihong Dong
- Shandong College of Traditional Chinese Medicine, Yantai, China
| | - Jing Cui
- The Third People's Hospital of Qingdao, Department of Emergency, Qingdao, China
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6
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Wu K, Hopkins BD, Sanchez R, DeVita RJ, Pan ZQ. Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators. JOURNAL OF CELLULAR SIGNALING 2021; 2:195-205. [PMID: 34604860 PMCID: PMC8486283 DOI: 10.33696/signaling.2.051] [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: 11/27/2022]
Abstract
Cullin-RING E3 ubiquitin ligase 4 (CRL4) plays an essential role in cell cycle progression. Recent efforts using high throughput screening and follow up hit-to-lead studies have led to identification of small molecules 33-11 and KH-4-43 that inhibit E3 CRL4's core ligase complex and exhibit anticancer potential. This review provides: 1) an updated perspective of E3 CRL4, including structural organization, major substrate targets and role in cancer; 2) a discussion of the challenges and strategies for finding the CRL inhibitor; and 3) a summary of the properties of the identified CRL4 inhibitors as well as a perspective on their potential utility to probe CRL4 biology and act as therapeutic agents.
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Affiliation(s)
- Kenneth Wu
- Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA
| | - Benjamin D Hopkins
- Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.,Genetics and Genomics, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA
| | - Roberto Sanchez
- Department of Pharmacological Sciences, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.,Drug Discovery Institute, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA
| | - Robert J DeVita
- Department of Pharmacological Sciences, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.,Drug Discovery Institute, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA
| | - Zhen-Qiang Pan
- Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA
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7
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Wang X, Chen T. CUL4A regulates endometrial cancer cell proliferation, invasion and migration by interacting with CSN6. Mol Med Rep 2020; 23:23. [PMID: 33179082 PMCID: PMC7673334 DOI: 10.3892/mmr.2020.11661] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 10/09/2020] [Indexed: 12/18/2022] Open
Abstract
Endometrial cancer (EC) is a common malignant gynecological tumor arising from the endometrium, with an annually increasing morbidity and mortality. The present study aimed to investigate the functions of cullin 4A (CUL4A) in EC, as well as the underlying mechanisms. CUL4A expression was assessed in several human EC cells and normal human endometrial epithelial cells (hEECs) via reverse transcription‑quantitative polymerase chain reaction and western blotting. Subsequently, short hairpin (sh)RNA‑CULA4 was transfected into cells, and cell proliferation, invasion and migration were detected using Cell Counting kit‑8, Transwell and wound healing assays, respectively. The STRING database identified that CSN6 interacted with CULA4, and immunoprecipitation was performed to verify the interaction. Subsequently, following CUL4A knockdown, pcDNA3.1‑CSN6 was transfected into cells and its effects on cell proliferation, invasion and migration were assessed. The expression levels of matrix metallopeptidase (MMP)2, MMP9 and p53 were evaluated via western blotting. The results indicated that CUL4A was highly expressed in EC cells, compared with hEECs. CULA4‑knockdown notably inhibited EC cell proliferation, invasion and migration. The expression levels of MMP2 and MMP9 were significantly decreased, while p53 expression was enhanced following CUL4A‑knockdown. The immunoprecipitation assay verified that COP9 signalosome subunit 6 (CSN6) interacted with CULA4. Furthermore, CSN6‑overexpression alleviated the inhibitory effects of CUL4A‑knockdown on EC cell proliferation, invasion and migration. Similarly, CSN6 overexpression reversed CUL4A‑knockdown‑mediated effects on the expression of MMP2, MMP9 and p53. In summary, the results demonstrated that CUL4A regulated EC cell proliferation, invasion and migration by interacting with CSN6.
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Affiliation(s)
- Xiangrong Wang
- Nursing Department, Jiangsu Union Technical Institute Nantong Health Branch, Nantong, Jiangsu 226010, P.R. China
| | - Tianquan Chen
- Department of Gynecology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
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8
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An amino-terminal BRAF deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer. Cold Spring Harb Mol Case Stud 2020; 6:mcs.a005140. [PMID: 32669268 PMCID: PMC7476412 DOI: 10.1101/mcs.a005140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 05/05/2020] [Indexed: 11/25/2022] Open
Abstract
Although combination therapy with RAF and EGFR inhibitors has improved the survival outcomes of patients with BRAF-mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating mutations in RASgenes, MAP2K mutations, and amplifications in BRAF, RAS genes, and EGFR. In this report, we describe a patient with BRAF-mutated CRC who acquired an amino-terminal BRAF deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy. Amino-terminal BRAF deletions involving the RBD are a rare mechanism of acquired resistance to RAF inhibitors, particularly in CRC for which there is only one prior report in the literature.
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9
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Moradpoor R, Gharebaghian A, Shahi F, Mousavi A, Salari S, Akbari ME, Ajdari S, Salimi M. Identification and Validation of Stage-Associated PBMC Biomarkers in Breast Cancer Using MS-Based Proteomics. Front Oncol 2020; 10:1101. [PMID: 32793473 PMCID: PMC7393188 DOI: 10.3389/fonc.2020.01101] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
Background: It is well-described that the transcriptome of peripheral blood mononuclear cells (PBMCs) can be altered in the context of many malignancies to allow them avoid the effective immune response, which leads to cancer invasiveness. Here, we used an MS-based strategy to discover biomarkers in the PBMCs of breast cancer (BC) patients and validated them at different stages of BC. Methods: PBMCs were isolated from the breast cancer patients and were cultured alone or co-cultured with breast cancer cell lines. The role of PBMC in the invasion property of breast cancer cells was explored. NF-kB activity was also measured in the co-cultured breast cancer cells. Identification of protein profiles in the secretome and proteome of the co-cultured PBMCs was performed using SWATH mass spectrometry. Pathway enrichment and gene ontology analyses were carried out to look for the molecular pathways correlated with the protein expression profile of PBMCs in the breast cancer patients. Quantitative real-time polymerase chain reaction (qPCR) was performed to validate the candidate genes in the PBMC fraction of the breast cancer patients at the primary and metastatic stages. In silico survival analysis was performed to assess the potential clinical biomarkers in these PBMC subtypes. Results: PBMCs could significantly increase the invasion property of the BC cells concomitant with a decrease in E-cadherin and an increase in both Vimentin and N-cadherin expression. The NF-kB activity in the BC cells significantly increased following co-culturing implying the role of PBMCs in EMT induction. Enrichment analysis showed that the differentially expressed proteins in PBMCs are mainly associated with IL-17, PI3K-Akt, and HIF-1 signaling pathway, in which a set of seven proteins including TMSB4X, HSPA4, S100A9, SRSF6, THBS1, CUL4A, and CANX were frequently expressed. Finally, in silico analysis confirmed that a gene set consisting of S100A9, SRSF6, THBS1, CUL4A, and CANX were found to provide an insight for the identification of metastasis in breast cancer patients. Conclusion: In conclusion, our study revealed that the protein expression profile in PBMCs is a reflection of the proteins expressed in the BC tissue itself; however, the abundance level is different due to the stage of cancer.
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Affiliation(s)
- Raheleh Moradpoor
- Department of Basic Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Gharebaghian
- Laboratory Hematology and Blood Bank Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farhad Shahi
- Breast Disease Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Asadollah Mousavi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sina Salari
- Medical Oncology, Hematology and Bone Marrow Transplantation, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Soheila Ajdari
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | - Mona Salimi
- Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran
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10
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Ye XD, Qiu BQ, Xiong D, Pei X, Jie N, Xu H, Zhu SQ, Long X, Xu Z, Wu HB, Xu JJ, Huang YS, Wu YB. High level of H3K4 tri-methylation modification predicts poor prognosis in esophageal cancer. J Cancer 2020; 11:3256-3263. [PMID: 32231731 PMCID: PMC7097960 DOI: 10.7150/jca.36801] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 02/04/2020] [Indexed: 01/23/2023] Open
Abstract
Objectives: An increase in the trimethylation of lysine 4 of histone 3 (H3K4me3) has been reported to be involved in the development of several types of tumors. However, the level and role of H3K4me3 in human esophageal cancer (HEC) remain unknown. Here, we assessed the role and clinical significance of H3K4me3 in HEC. Methods: The level of H3K4me3 was determined in 15 pairs of HEC and paracancerous tissues by Western blotting. A tissue microarray including samples from 100 HEC patients was analyzed by immunohistochemistry to determine the relationship between the level of H3K4me3 and the clinicopathological features of HEC patients. Then, the levels of H3K4me3 in HEC cells were elevated via knockdown of inhibitor of growth family member 4(Ing4) expression. Finally, the prognostic significance of H3K4me3 levels in HEC patients was further analyzed. Results: We found that H3K4me3 levels were frequently elevated in HEC tissues compared with adjacent esophageal tissues, and elevated H3K4me3 was significantly associated with poor tumor differentiation (p =1.39×10-5) and advanced tumor stage (p=8.5×10-5). After Ing4 knockdown in HEC cells, we found that the cell proliferation, metastasis, invasion and colony formation abilities were enhanced compared to those in the control cells. Notably, we found that HEC patients with a high level of H3K4me3 exhibited an unfavorable 5-year survival rate compared to those with a low level of H3K4me3 (p=6.8×10-5). The univariate analysis showed that the tumor differentiation, TNM stage, and H3K4me3 level were predictors of the overall survival rate of HEC patients. In the multivariate analysis, tumor stage (p=0.015) and H3K4me3 level (p=0.034) were revealed to be independent parameters for predicting the prognosis of HEC patients. Conclusions: Thus, high levels of H3K4me3 may be used as a meaningful biomarker for HEC prognosis evaluation.
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Affiliation(s)
- Xu-Dong Ye
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Bai-Quan Qiu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Dian Xiong
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China.,Department of Thoracic Surgery, The Central Hospital of Xuhui District, Shanghai, 20031, P. R. China
| | - Xu Pei
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Na Jie
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan 571101, P.R. China
| | - Hua Xu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Shu-Qiang Zhu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Xiang Long
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Zheng Xu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Hai-Bo Wu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - Jian-Jun Xu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
| | - You-Sheng Huang
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan 571101, P.R. China
| | - Yong-Bing Wu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, P. R. China
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Abstract
Cullin-RING ligase 4 (CRL4), a member of the cullin-RING ligase family, orchestrates a variety of critical cellular processes and pathophysiological events. Recent results from mouse genetics, clinical analyses, and biochemical studies have revealed the impact of CRL4 in development and cancer etiology and elucidated its in-depth mechanism on catalysis of ubiquitination as a ubiquitin E3 ligase. Here, we summarize the versatile roles of the CRL4 E3 ligase complexes in tumorigenesis dependent on the evidence obtained from knockout and transgenic mouse models as well as biochemical and pathological studies.
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Chen B, Feng Y, Zhang M, Cheng G, Chen B, Wang H. Small molecule TSC01682 inhibits osteosarcoma cell growth by specifically disrupting the CUL4B-DDB1 interaction and decreasing the ubiquitination of CRL4B E3 ligase substrates. Am J Cancer Res 2019; 9:1857-1870. [PMID: 31598391 PMCID: PMC6780663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 08/26/2019] [Indexed: 06/10/2023] Open
Abstract
The direct interaction between Cullin 4B (CUL4B) and DNA damage-binding protein 1 (DDB1) is required for the assembly of Cullin4B-RING E3 ligase complex (CRL4B), which are involved in the tumorigenesis of osteosarcoma through ubiquitinating and degrading multiple tumor suppressors and cell cycle regulators. Thus, targeting CUL4B-DDB1 interaction to prevent the assembly of CRL4B may be a potent approach to inhibit osteosarcoma cell growth. In the present study, we identified six naturally-sourced small molecules that can specifically disrupt the CUL4B-DDB1 interaction using an in vitro high-throughput screening (HTS) system in yeast. We focused our investigation on revealing the molecular effects of TSC01682, the most active compound capable of inhibiting osteosarcoma cell growth. Biochemically, TSC01682 significantly repressed the CUL4B-DDB1 interaction in both yeast cells and osteosarcoma cells. Moreover, TSC01682 treatment in osteosarcoma cells also caused a decrease of other CRL4B components including CUL4-associated factor 11 (DCAF11) and DCAF13, but an increase of two CRL4B substrates including cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through inhibiting their ubiquitination. Consistent with these molecular changes, TSC01682 treatment significantly inhibited cell proliferation, colony formation, invasion, and in vivo tumor growth. Collectively, our results suggest that TSC01682 is a potent compound capable of disrupting the CUL4B-DDB1 interaction, and it may be developed as a chemotherapeutic drug for osteosarcoma treatment.
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Affiliation(s)
- Bin Chen
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China
| | - Yu Feng
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China
| | - Meimei Zhang
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China
| | - Guangqi Cheng
- Department of Orthopaedics, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China
| | - Bin Chen
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China
| | - Hantao Wang
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China
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Hung MS, Chen YC, Lin P, Li YC, Hsu CC, Lung JH, You L, Xu Z, Mao JH, Jablons DM, Yang CT. Cul4A Modulates Invasion and Metastasis of Lung Cancer Through Regulation of ANXA10. Cancers (Basel) 2019; 11:618. [PMID: 31052599 PMCID: PMC6562482 DOI: 10.3390/cancers11050618] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/15/2019] [Accepted: 04/24/2019] [Indexed: 02/06/2023] Open
Abstract
: Cullin 4A (Cul4A) is overexpressed in a number of cancers and has been established as an oncogene. This study aimed to elucidate the role of Cul4A in lung cancer invasion and metastasis. We observed that Cul4A was overexpressed in non-small cell lung cancer (NSCLC) tissues and the overexpression of Cul4A was associated with poor prognosis after surgical resection and it also decreased the expression of the tumor suppressor protein annexin A10 (ANXA10). The knockdown of Cul4A was associated with the upregulation of ANXA10, and the forced expression of Cul4A was associated with the downregulation of ANXA10 in lung cancer cells. Further studies showed that the knockdown of Cul4A inhibited the invasion and metastasis of lung cancer cells, which was reversed by the further knockdown of ANXA10. In addition, the knockdown of Cul4A inhibited lung tumor metastasis in mouse tail vein injection xenograft models. Notably, Cul4A regulated the degradation of ANXA10 through its interaction with ANXA10 and ubiquitination in lung cancer cells. Our findings suggest that Cul4A is a prognostic marker in NSCLC patients, and Cul4A plays important roles in lung cancer invasion and metastasis through the regulation of the ANXA10 tumor suppressor.
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Affiliation(s)
- Ming-Szu Hung
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi branch 61363, Taiwan.
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
- Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi 61363, Taiwan.
| | - Yi-Chuan Chen
- Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi branch 61363, Taiwan.
| | - PaulYann Lin
- Department of Anatomic Pathology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 62247, Taiwan.
| | - Ya-Chin Li
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi branch 61363, Taiwan.
| | - Chia-Chen Hsu
- Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi branch 61363, Taiwan.
- Department of Medical Research and Development, Chang Gung Memorial Hospital, Chiayi branch 61363, Taiwan.
| | - Jr-Hau Lung
- Department of Medical Research and Development, Chang Gung Memorial Hospital, Chiayi branch 61363, Taiwan.
| | - Liang You
- Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
| | - Zhidong Xu
- Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
| | - Jian-Hua Mao
- Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA 94720, USA.
| | - David M Jablons
- Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
| | - Cheng-Ta Yang
- Department of Respiratory Care, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
- Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan branch 33378, Taiwan.
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Liu H, Lu W, He H, Wu J, Zhang C, Gong H, Yang C. Inflammation-dependent overexpression of c-Myc enhances CRL4 DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis-associated cancer. J Pathol 2019; 248:464-475. [PMID: 30945288 DOI: 10.1002/path.5273] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 03/04/2019] [Accepted: 04/01/2019] [Indexed: 02/05/2023]
Abstract
Inflammation is well known as an important driver of the initiation of colitis-associated cancer (CAC). Some cytokines, such as IL-6 and TNF-α can activate expression of the oncogene c-Myc (MYC) and regulate its downstream effects. Cullin-RING E3 Ligases (CRLs) are emerging as master regulators controlling tumorigenesis. Here, we demonstrate that two cullin genes, CUL4A and CUL4B, but not other members, are specifically overexpressed in CAC tumour samples and positively correlate with levels of the proinflammatory cytokines IL-1β and IL-6. In vitro experiments revealed that the transcription factor c-Myc can specifically activate the expression of CUL4A and CUL4B by binding to a conserved site (CACGTG) located in their promoters. Additionally, we found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). Overexpression of c-Myc in human colon epithelial cells resulted in the accumulation of CUL4A, CUL4B and DCAF4, but degradation of ST7. In contrast, knockdown of c-Myc, CUL4A or CUL4B in the colon adenocarcinoma cell line HT29 caused accumulation of ST7 and inhibition of cell proliferation, colony formation ability and in vivo tumour growth. Collectively, our results provide in vitro and in vivo evidence that c-Myc regulates CRL4DCAF4 E3 ligase activity to mediate ubiquitination of ST7, whose presence is physiologically essential for CAC tumorigenesis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Hong Liu
- Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Wenzhu Lu
- Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Hongbo He
- Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Jin Wu
- Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Caiguo Zhang
- Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Hanlin Gong
- Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Chunmei Yang
- Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
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Chen Z, Han Y, Deng C, Chen W, Jin L, Chen H, Wang K, Shen H, Qian L. Inflammation‐dependent downregulation of miR‐194‐5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B. J Cell Physiol 2019; 234:19977-19989. [PMID: 30945295 DOI: 10.1002/jcp.28595] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/07/2019] [Accepted: 03/19/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Zhi Chen
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Yingchao Han
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Chao Deng
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Wei Chen
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Linyu Jin
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Hao Chen
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Kun Wang
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Hongxing Shen
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
| | - Lie Qian
- Department of Spine Surgery Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai China
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Cheng J, Guo J, North BJ, Tao K, Zhou P, Wei W. The emerging role for Cullin 4 family of E3 ligases in tumorigenesis. Biochim Biophys Acta Rev Cancer 2018; 1871:138-159. [PMID: 30602127 DOI: 10.1016/j.bbcan.2018.11.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 11/28/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023]
Abstract
As a member of the Cullin-RING ligase family, Cullin-RING ligase 4 (CRL4) has drawn much attention due to its broad regulatory roles under physiological and pathological conditions, especially in neoplastic events. Based on evidence from knockout and transgenic mouse models, human clinical data, and biochemical interactions, we summarize the distinct roles of the CRL4 E3 ligase complexes in tumorigenesis, which appears to be tissue- and context-dependent. Notably, targeting CRL4 has recently emerged as a noval anti-cancer strategy, including thalidomide and its derivatives that bind to the substrate recognition receptor cereblon (CRBN), and anticancer sulfonamides that target DCAF15 to suppress the neoplastic proliferation of multiple myeloma and colorectal cancers, respectively. To this end, PROTACs have been developed as a group of engineered bi-functional chemical glues that induce the ubiquitination-mediated degradation of substrates via recruiting E3 ligases, such as CRL4 (CRBN) and CRL2 (pVHL). We summarize the recent major advances in the CRL4 research field towards understanding its involvement in tumorigenesis and further discuss its clinical implications. The anti-tumor effects using the PROTAC approach to target the degradation of undruggable targets are also highlighted.
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Affiliation(s)
- Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jianping Guo
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Brian J North
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Pengbo Zhou
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA.
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Chen D, You X, Pan Y, Liu Q, Cao G. TRIM37 promotes cell invasion and metastasis by regulating SIP1-mediated epithelial-mesenchymal transition in gastric cancer. Onco Targets Ther 2018; 11:8803-8813. [PMID: 30573971 PMCID: PMC6292391 DOI: 10.2147/ott.s178446] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Background Tripartite motif containing 37 (TRIM37) has been demonstrated to function importantly during the progression of various cancers. However, the role of TRIM37 in gastric cancer (GC) remains elusive. Materials and methods TRIM37 mRNA and protein expressions were determined by qRT-PCR, Western blot, and immunohistochemical staining in GC specimens. The effects of TRIM37 on GC cells behavior were evaluated by transwell assays in vitro and metastasis assay in vivo, respectively. Besides, qRT-PCR, Western blot, and immunofluorescence staining were employed to detect the expressions of TRIM37 and epithelial–mesenchymal transition (EMT)-related markers. Results The present study revealed that TRIM37 mRNA or protein expression was significantly increased in GC tissues compared with that in paracancerous control tissues, and its aberrant overexpression was closely associated with clinical metastasis and poor prognosis in patients with GC. TRIM37 knockdown significantly suppressed GC cells migration and invasion in vitro, as well as metastasis in vivo. Inversely, TRIM37 overexpression exerted the opposite effects. Mechanistic studies suggested that SIP1-mediated EMT might be responsible for TRIM37-facilitated GC cells migration and invasion. Conclusion Our findings revealed that high TRIM37 expression was associated with clinical metastasis and poor survival in patients with GC. TRIM37 promoted GC cells migration and invasion via EMT, mediated by the transcription factor SIP1, thus providing a candidate target for GC treatment.
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Affiliation(s)
- Dehu Chen
- Department of General Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, Jiangsu Province, People's Republic of China,
| | - Xiaolan You
- Department of General Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, Jiangsu Province, People's Republic of China,
| | - Yan Pan
- Department of General Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, Jiangsu Province, People's Republic of China,
| | - Qinghong Liu
- Department of General Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, Jiangsu Province, People's Republic of China,
| | - Gan Cao
- Department of General Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, Jiangsu Province, People's Republic of China,
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