Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas

Jian Pan, Tiago C. Silva, Nicole Gull, Qian Yang, Jasmine T. Plummer, Stephanie Chen, Kenji Daigo, Takao Hamakubo, Sigal Gery, Ling Wen Ding, Yan Yi Jiang, Shaoyan Hu, Li Yan Xu, En Min Li, Yanbing Ding, Samuel J. Klempner, Simon A. Gayther, Benjamin P. Berman*, H. Phillip Koeffler, De Chen Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract including 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.

Original languageAmerican English
Pages (from-to)2722-2736
Number of pages15
JournalCancer Research
Issue number13
StatePublished - 1 Jul 2020

Bibliographical note

Funding Information:
This work was supported by NIH grant (1R01 CA200992) to H.P. Koeffler and the National Research Foundation Singapore under its Singapore Translational Research Investigator Award (NMRC/STaR/0021/2014 to H.P. Koeffler) and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC); the NMRC Centre Grant awarded to National University Cancer Institute; the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives to H.P. Koeffler. D-C. Lin is supported by the DeGregorio Family Foundation, the Price Family Foundation, Samuel Oschin Comprehensive Cancer Institute SOCCI through the Translational Pipeline Discovery Fund. He is a member of UCLA Jonsson Comprehensive Cancer Center, UCLA Molecular Biology Institute as well as UCLA Cure: Digestive Disease Research Center. B.P. Berman and T.C. Silva were supported by the Genomic Data Analysis Network of the NCI via grant U24CA210969. N. Gull was supported by institutional funding from the Cedars-Sinai Center for Bioinformatics and Functional Genomics. This research was also partly supported by National Natural Science Foundation of China (NSFC; Nos. 81570125, 81770145), Jiangsu province's science and technology support program (Social Development) project (BE2017658), and the philanthropic donations from the Melamed family. S.J. Klempner was supported by the Howard H. Hall fund for esophageal cancer research.

Publisher Copyright:
© 2020 American Association for Cancer Research.


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