Reference - Detail
| RRC ID | 60104 |
|---|---|
| Author | Xu C, Ooi WF, Qamra A, Tan J, Chua BY, Ho SWT, Das K, Adam Isa ZF, Li Z, Yao X, Yan T, Xing M, Huang KK, Lin JS, Nandi T, Tay ST, Lee MH, Tan ALK, Ong X, Ashktorab H, Smoot D, Li S, Ng SC, Teh BT, Tan P. |
| Title | HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer. |
| Journal | Gut |
| Abstract |
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. |
| Volume | 69(2) |
| Pages | 231-242 |
| Published | 2020-2-1 |
| DOI | 10.1136/gutjnl-2018-318025 |
| PII | gutjnl-2018-318025 |
| PMID | 31068366 |
| MeSH | Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use Cell Line, Tumor Enzyme Inhibitors / pharmacology Enzyme Inhibitors / therapeutic use Female Gene Expression Profiling / methods Gene Expression Regulation, Neoplastic Gene Targeting / methods Hepatocyte Nuclear Factor 4 / genetics* Hepatocyte Nuclear Factor 4 / metabolism Humans Isocitrate Dehydrogenase / antagonists & inhibitors Isocitrate Dehydrogenase / metabolism* Mice, Inbred NOD Molecular Targeted Therapy / methods Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Promoter Regions, Genetic / genetics Stomach Neoplasms / drug therapy Stomach Neoplasms / genetics* Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Up-Regulation / genetics Xenograft Model Antitumor Assays |
| Resource | |
| Human and Animal Cells | LMSU(RCB1062) |