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HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer

Author

Listed:
  • Qing Xu

    (National Institute of Environmental Health Sciences)

  • Yuanyuan Li

    (National Institute of Environmental Health Sciences)

  • Xia Gao

    (Duke University School of Medicine)

  • Kai Kang

    (National Institute of Environmental Health Sciences)

  • Jason G. Williams

    (National Institute of Environmental Health Sciences)

  • Lingfeng Tong

    (Shanghai Jiao Tong University School of Medicine)

  • Juan Liu

    (Duke University School of Medicine)

  • Ming Ji

    (National Institute of Environmental Health Sciences)

  • Leesa J. Deterding

    (National Institute of Environmental Health Sciences)

  • Xuemei Tong

    (Shanghai Jiao Tong University School of Medicine)

  • Jason W. Locasale

    (Duke University School of Medicine)

  • Leping Li

    (National Institute of Environmental Health Sciences)

  • Igor Shats

    (National Institute of Environmental Health Sciences)

  • Xiaoling Li

    (National Institute of Environmental Health Sciences)

Abstract

Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism, increases resistance to methionine restriction or sorafenib, promotes epithelial-mesenchymal transition, and induces cell migration. Conversely, genetic or metabolic restoration of the transsulfuration pathway in SAA metabolism significantly alleviates the outcomes induced by HNF4α deficiency in liver cancer cells. Our study identifies HNF4α as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.

Suggested Citation

  • Qing Xu & Yuanyuan Li & Xia Gao & Kai Kang & Jason G. Williams & Lingfeng Tong & Juan Liu & Ming Ji & Leesa J. Deterding & Xuemei Tong & Jason W. Locasale & Leping Li & Igor Shats & Xiaoling Li, 2020. "HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17818-w
    DOI: 10.1038/s41467-020-17818-w
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    Cited by:

    1. Ying Huang & Geng Qin & TingTing Cui & Chuanqi Zhao & Jinsong Ren & Xiaogang Qu, 2023. "A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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