Journal Article

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

Tan, Angie Lay Keng, Ong, Xuewen, Qamra, Aditi, Teh, Bin Tean, Chua, Benjamin Yan-Jiang, Li, Shang, Das, Kakoli, Adam Isa, Zul Fazreen, Smoot, Duane, Ng, Shyh-Chang, Tan, Jing, Huang, Kie Kyon, Yan, Tingdong, Tay, Su Ting, Yao, Xiaosai, Ho, Shamaine Wei Ting, Xing, Manjie, Lee, Ming Hui, Nandi, Tannistha, Tan, Patrick, Xu, Chang, Ooi, Wen Fong, Lin, Joyce Suling, Ashktorab, Hassan, Li, Zhimei

2020

Overview

ObjectiveGastric 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.DesignWe 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.ResultsGene 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.ConclusionsOur 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Binding sites / Biomarkers / Cell Line, Tumor / Cell survival / Chromatin / Dehydrogenases / Drug delivery / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Experiments / Female / Gastric cancer / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation, Neoplastic / Gene mapping / Gene Targeting - methods / Genomes / Genomics / Hepatocyte Nuclear Factor 4 - genetics / Hepatocyte Nuclear Factor 4 - metabolism / Humans / Immunoprecipitation / Isocitrate dehydrogenase / Isocitrate Dehydrogenase - antagonists & inhibitors / Isocitrate Dehydrogenase - metabolism / Mass spectrometry / Metabolism / Metabolomics / Mice, Inbred NOD / Molecular Targeted Therapy - methods / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Promoter Regions, Genetic - genetics / Scientific imaging / Stomach / Stomach Neoplasms - drug therapy / Stomach Neoplasms - genetics / Stomach Neoplasms - metabolism / Stomach Neoplasms - pathology / Studies / Tumors / Up-Regulation - genetics / Xenograft Model Antitumor Assays / Xenografts