Journal
CANCER RESEARCH
Volume 80, Issue 13, Pages 2722-2736Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-0390
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Funding
- NIH [1R01 CA200992]
- National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014]
- NMRC Centre Grant
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiatives
- DeGregorio Family Foundation
- Price Family Foundation
- Samuel Oschin Comprehensive Cancer Institute SOCCI through the Translational Pipeline Discovery Fund
- Genomic Data Analysis Network of the NCI [U24CA210969]
- Cedars-Sinai Center for Bioinformatics and Functional Genomics
- National Natural Science Foundation of China (NSFC) [81570125, 81770145]
- Jiangsu province's science and technology support program (Social Development) project [BE2017658]
- Howard H. Hall fund for esophageal cancer research
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Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract induding esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6, and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers. Significance: These findings show that GIAC-specific master regulatory transcription factors control HNF4A via three distal enhancers to promote GIAC cell proliferation and survival.
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