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

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 () and Xiaoling Li ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17818-w

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