<i>HNF4α</i> pathway mapping identifies wild-type <i>IDH1</i> as a targetable metabolic node in gastric cancer.

Abstract

Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that <i>hepatocyte nuclear factor-4α (HNF4α)</i> 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. 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 <i>in vitro</i> and <i>in vivo</i> relevance. To investigate mechanistic roles of <i>HNF4α</i> and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments. Gene expression analysis across 19 tumour types revealed <i>HNF4α</i> to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top <i>HNF4α</i>-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (<i>IDH1</i>) emerged as a convergent <i>HNF4α</i> direct target gene regulating GC metabolism. We show that wild-type <i>IDH1</i> is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors. Our results highlight a role for <i>HNF4α</i> in sustaining GC oncogenic metabolism, through the regulation of <i>IDH1</i>. Drugs targeting wild-type <i>IDH1</i> may thus have clinical utility in GCs exhibiting <i>HNF4α</i> overexpression, expanding the role of <i>IDH1</i> in cancer beyond <i>IDH1/2</i> mutated malignancies.