Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer
| العنوان: | Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer |
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| المؤلفون: | Zul Fazreen Adam Isa, Mandoli Amit, Aditi Qamra, Mei Mei Chang, Nisha Padmanabhan, Kakoli Das, Jing Wang, Mohana Ray, Angie Lay Keng Tan, Giovani Claresta Wijaya, Michael A. Beer, Shamaine Wei Ting Ho, Xuewen Ong, Patrick Tan, Ming Hui Lee, Jing Tan, Kie Kyon Huang, Bin Tean Teh, Chukwuemeka George Anene-Nzelu, Taotao Sheng, Zhimei Li, Heike I. Grabsch, Polly Poon, Su Ting Tay, Shenli Zhang, Shang Li, Tannistha Nandi, Jing Quan Lim, Xiaosai Yao, Po Hsien Lee, Wen Fong Ooi, Kevin P. White, Roger Foo, Tingdong Yan, Ley Moy Ng, Gregorio E. Fazzi, Steven G. Rozen, Jeanie Wu, Yu Amanda Guo, Manjie Xing, Kevin Lim, Lijia Ma, Yue Ning Lam, Joyce Suling Lin, Anders Jacobsen Skanderup, Chang Xu |
| المساهمون: | Pathologie, RS: GROW - R2 - Basic and Translational Cancer Biology |
| المصدر: | J Clin Invest Journal of Clinical Investigation, 130(6), 3005-3020. American Society for Clinical Investigation |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Epigenomics, Somatic cell, GROUP PROTEIN EZH2, Repressor, PROGRESSION, CAPECITABINE, Biology, TELOMERASE ACTIVITY, Response Elements, DNA methyltransferase, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, 0302 clinical medicine, Stomach Neoplasms, Cell Line, Tumor, medicine, Humans, Transcription factor, Telomerase, RECOGNITION, Cancer, General Medicine, PROMOTER MUTATIONS, CHEMOTHERAPY, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, TRANSCRIPTION FACTORS, 030104 developmental biology, DIFFERENTIATION, 030220 oncology & carcinogenesis, B-CELL FACTOR-1, Mutation, Cancer research, biology.protein, Trans-Activators, Histone deacetylase activity, PRC2, Research Article |
| الوصف: | Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA-binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1. |
| وصف الملف: | application/pdf |
| تدمد: | 1558-8238 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5ad4af4c0f72d99bfe48547ad2ad15e6 https://pubmed.ncbi.nlm.nih.gov/32364535 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....5ad4af4c0f72d99bfe48547ad2ad15e6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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