CHARACTERIZATION OF HNF4a IN GASTRIC CANCER METABOLISM

Abstract

Hepatocyte nuclear factor-4α (HNF4α) is frequently overexpressed in gastric cancer (GC) and required for various GC malignant features. However, therapeutic opportunities for HNF4α-positive GCs remain obscure. Combining HNF4α chromatin immunoprecipitation followed by sequencing (ChIP-seq) of multiple GC cell lines with (epi)genomic and transcriptome data of primary GCs, we uncovered HNF4α as a pivotal regulator of organic acid metabolism. Metabolomic analysis, coupled with metabolite rescue assays, identified specific HNF4α-dependent metabolic alterations functionally required for GC development. We identified wild-type isocitrate dehydrogenase 1 (IDH1) as a direct HNF4α target gene required for GC survival in vitro and in vivo while sparing normal gastric epithelial cells, and demonstrate that high IDH1-expressing GC cells levels exhibit enhanced sensitivity to IDH1 genetic and pharmacologic inhibition. Our results highlight HNF4α as a pivotal regulator of specific metabolic hallmarks of GC, and wild-type IDH1 as a targetable metabolic node in HNF4α-positive tumors.