Abstract：
: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. SIGNIFICANCE: These findings show that GIAC-specific master regulatory transcription factors control HNF4A via three distal enhancers to promote GIAC cell proliferation and survival. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2722/F1.large.jpg.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Pan J,Silva TC,Gull N,Yang Q,Plummer JT,Chen S,Daigo K,Hamakubo T,Gery S,Ding LW,Jiang YY,Hu S,Xu LY,Li EM,Ding Y,Klempner SJ,Gayther SA,Berman BP,Koeffler HP,Lin DCdoi
10.1158/0008-5472.CAN-20-0390subject
Has Abstractpub_date
2020-07-01 00:00:00pages
2722-2736issue
13eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-20-0390journal_volume
80pub_type
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