Lineage-Specific Epigenomic and Genomic Activation of the Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Backgrounds</jats:title><jats:p>Gastrointestinal adenocarcinomas (GIACs) of the tubular 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 GIACs are less well-characterized.We applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks using 907 GIAC samples from The Cancer Genome Atlas (TCGA). Complementary epigenomic technologies were performed to investigate HNF4A activation, including Circularized Chromosome Conformation Capture (4C), Chromatin immunoprecipitation (ChIP) sequencing, Whole Genome Bisulfite Sequencing (WGBS), and Assay for Transposase-Accessible Chromatin (ATAC) sequencing. In vitro and in vivo cellular phenotypical assays were conducted to study HNF4A functions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified a list of functionally hyperactive master regulator (MR)TFs shared across different GIACs. As the top candidate, HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. We further characterized a complex interplay between HNF4A promoter and three distal enhancer elements, which was coordinated by GIAC-specific MRTFs including ELF3, GATA4, GATA6 and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptionally activating many downstream targets including HNF1A and factors of Interleukin signaling in a lineage-specific manner.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We use a large cohort of patient samples and an unbiased mathematical approach to highlight lineage-specific oncogenic MRTFs, which provide new insights into the GIAC-specific gene regulatory networks, and identify potential therapeutic strategies against these common cancers.</jats:p></jats:sec>

Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology

“…In contrast to HCC, where an overall diminished HNF4A signaling is observed in most studies, as discussed above, several gastrointestinal adenocarcinomas (GIAC) including esophageal, gastric, pancreatic, and colorectal adenocarcinomas are characterized by increased HNF4A expression [ 181 , 182 ]. This finding was recently confirmed by a large-scale transcriptomic and DNA methylomic study on 907 GIAC samples from The Cancer Genome Atlas [ 153 ]. The latter work furthermore revealed that HNF4A overexpression in GIAC was driven by both genomic and epigenomic mechanisms, as illustrated by the high prevalence of HNF4A gene locus amplification in GIAC and the increased chromatin accessibility of its promoter, respectively.…”

“…In line with the HNF4A loss observed in chronic liver injuries, a number of studies have reported decreased HNF4A expression in HCC. Indeed, lower HNF4A transcript levels were found in rodent models of hepatocarcinogenesis, as well as in HCC patients [ 151 , 152 , 153 ], although not all studies concur [ 154 ]. Consistent with HNF4A being a liver tumor suppressor, deletion of Hnf4a promotes the occurrence of HCC in mice [ 155 , 156 ].…”

“…In summary, the abovementioned findings point towards a reduced HNF4A signaling in HCC and demonstrate a key role for HNF4A in HCC progression through modulation of EMT, cell proliferation, apoptosis, and inflammation. In line with HNF4A’s role in controlling identity of additional endodermal organs, diminished HNF4A expression is likewise found in renal cancers and cholangiocarcinoma [ 153 ]. Interestingly, the molecular mechanisms underlying the persistent downregulation of HNF4A in chronic liver injuries and HCC may at least partly differ from the repressive mechanisms triggered by acute tissue damage described in the previous section.…”

“…The latter work furthermore revealed that HNF4A overexpression in GIAC was driven by both genomic and epigenomic mechanisms, as illustrated by the high prevalence of HNF4A gene locus amplification in GIAC and the increased chromatin accessibility of its promoter, respectively. In line with its expression being increased in GIAC, inhibition of HNF4A signaling suppressed the growth of GIAC cancer cells and xenografts [ 153 , 183 ]. Conversely, overexpression of HNF4A in adult mouse esophageal explants induced a columnar-like expression profile [ 184 ] and HNF4A alone was sufficient to drive chromatin opening and activation of a esophageal adenocarcinoma-like chromatin signature when expressed in normal human epithelial cells [ 185 ], suggestive of a key role for HNF4A in promoting GIAC initiation and progression.…”

Core transcriptional regulatory circuitries in cancer

“…Consistent with substantial involvement of these core TFs in EAC transcriptome, they played positive roles to maintain survival and proliferation of EAC cells. SE-driven LIF, LIFR and HNF4A represented leading candidates for CRC downstream targets which exhibited both disease-specificity and therapeutic venerability [ 71 , 73 ].…”