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Original research
HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer
  1. Chang Xu1,2,
  2. Wen Fong Ooi3,
  3. Aditi Qamra3,4,
  4. Jing Tan5,6,
  5. Benjamin Yan-Jiang Chua7,
  6. Shamaine Wei Ting Ho1,2,
  7. Kakoli Das2,
  8. Zul Fazreen Adam Isa2,
  9. Zhimei Li5,
  10. Xiaosai Yao8,
  11. Tingdong Yan2,
  12. Manjie Xing2,4,
  13. Kie Kyon Huang2,
  14. Joyce Suling Lin3,
  15. Tannistha Nandi3,
  16. Su Ting Tay2,
  17. Ming Hui Lee2,
  18. Angie Lay Keng Tan2,
  19. Xuewen Ong2,
  20. Hassan Ashktorab9,
  21. Duane Smoot10,
  22. Shang Li2,11,
  23. Shyh-Chang Ng7,
  24. Bin Tean Teh1,2,5,8,11,
  25. Patrick Tan1,2,3,12,13,14
  1. 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
  2. 2 Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore
  3. 3 Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore
  4. 4 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
  5. 5 Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore, Singapore
  6. 6 State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
  7. 7 Agency for Science Technology and Research, Genome Institute of Singapore, Singapore, Singapore
  8. 8 Institute of Molecular and Cell Biology, Singapore, Singapore
  9. 9 Department of Medicine, Howard University, Washington, DC, USA
  10. 10 Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, USA
  11. 11 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  12. 12 SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore
  13. 13 Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore
  14. 14 Singapore Gastric Cancer Consortium, Singapore, Singapore
  1. Correspondence to Dr Patrick Tan, Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169610, Singapore; gmstanp{at}duke-nus.edu.sg

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.

  • gastric cancer
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Footnotes

  • CX and WFO contributed equally.

  • Contributors CX, WFO and PT designed experiments, performed the data analysis and interpretation. CX, JT, SWTH, KD, ZFAI and ZL conducted experiments. WFO, AQ, JSL and TN contributed to the data analysis of high-throughput sequencing. BYC, XY, TY, MX, KKH, STT, MHL, ALKT, XO, HA, DS, SL, SCN and BTT provided facilities, reagents and intellectual input. CX, WFO and PT wrote and edited the manuscript. CX and WFO contributed equally to this article.

  • Funding This work is supported by the Cancer Science Institute of Singapore, NUS, under the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, and the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme administered by the Singapore Ministry of Health’s National Medical Research Council (TCR/009-NUHS/2013), NMRC/STaR/0026/2015.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Author note The data generated for this study are deposited in GSE114018.

  • Patient consent for publication Not required.

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