Objective Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4α (HNF4α) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes.
Design We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4α and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments.
Results Gene expression analysis across 19 tumour types revealed HNF4α to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4α-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (IDH1) emerged as a convergent HNF4α direct target gene regulating GC metabolism. We show that wild-type IDH1 is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors.
Conclusions Our results highlight a role for HNF4α in sustaining GC oncogenic metabolism, through the regulation of IDH1. Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4α overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.
- gastric cancer
Statistics from Altmetric.com
CX and WFO contributed equally.
Contributors CX, WFO and PT designed experiments, performed the data analysis and interpretation. CX, JT, SWTH, KD, ZFAI and ZL conducted experiments. WFO, AQ, JSL and TN contributed to the data analysis of high-throughput sequencing. BYC, XY, TY, MX, KKH, STT, MHL, ALKT, XO, HA, DS, SL, SCN and BTT provided facilities, reagents and intellectual input. CX, WFO and PT wrote and edited the manuscript. CX and WFO contributed equally to this article.
Funding This work is supported by the Cancer Science Institute of Singapore, NUS, under the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, and the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme administered by the Singapore Ministry of Health’s National Medical Research Council (TCR/009-NUHS/2013), NMRC/STaR/0026/2015.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Author note The data generated for this study are deposited in GSE114018.
Patient consent for publication Not required.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.