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

IDH1 生物 癌症研究 异柠檬酸脱氢酶 癌症 基因 遗传学 突变 生物化学
作者
Chang Xu,Wen Fong Ooi,Aditi Qamra,Jing Tan,Yan‐Jiang Benjamin Chua,Shamaine Wei Ting Ho,Kakoli Das,Zul Fazreen Adam Isa,Zhimei Li,Xiaosai Yao,Tingdong Yan,Manjie Xing,Kie Kyon Huang,Joyce Suling Lin,Tannistha Nandi,Su Ting Tay,Ming Hui Lee,Angie Lay Keng Tan,Xuewen Ong,Hassan Ashktorab,Duane T. Smoot,Shang Li,Ng Shyh‐Chang,Bin Tean Teh,Patrick Tan
出处
期刊:Gut [BMJ]
卷期号:69 (2): 231-242 被引量:29
标识
DOI:10.1136/gutjnl-2018-318025
摘要

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.
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