Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer
- 1 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (6), 3005-3020
- https://doi.org/10.1172/jci126726
Abstract
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.Funding Information
- National Medical Research Council (TCR/009-NUHS/2013,NMRC/STaR/0026/2015)
- National University Cancer Institute, Singapore (NR13NMR111OM)
- National Medical Research Council (OFLCG18May-0003,OFIRG15nov072)
- Agency for Science, Technology and Research (GAP fund ETPL/15-R15 GAP-0021)
- Ministry of Education Academic Research, Singapore (MOE2017-T2-1-105)
- Guangdong Innovative and Entrepreneurial Research Team Program, China (2016ZT06S638,2016ZT06S252)
- National Natural Science Foundation of China (61661146004)
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