HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer

Objective Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4 alpha (HNF4 alpha) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4 alpha and oncogenic pathways driven by HNF4 alpha and HNF4 alpha target genes. Design We performed HNF4 alpha chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4 alpha occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4 alpha target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4 alpha and HNF4 alpha targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments. Results Gene expression analysis across 19 tumour types revealed HNF4 alpha to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4 alpha-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (IDH1) emerged as a convergent HNF4 alpha 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 HNF4 alpha in sustaining GC oncogenic metabolism, through the regulation of IDH1. Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4 alpha overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.