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

Publication ,  Journal Article
Xu, Q; Li, Y; Gao, X; Kang, K; Williams, JG; Tong, L; Liu, J; Ji, M; Deterding, LJ; Tong, X; Locasale, JW; Li, L; Shats, I; Li, X
Published in: Nature communications
August 2020

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.

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Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

August 2020

Volume

11

Issue

1

Start / End Page

3978

Related Subject Headings

  • Transcription, Genetic
  • Sorafenib
  • Mice
  • Methionine
  • Metabolome
  • Metabolic Networks and Pathways
  • Mesoderm
  • Liver Neoplasms
  • Liver
  • Hepatocyte Nuclear Factor 4
 

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Xu, Q., Li, Y., Gao, X., Kang, K., Williams, J. G., Tong, L., … Li, X. (2020). HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer. Nature Communications, 11(1), 3978. https://doi.org/10.1038/s41467-020-17818-w
Xu, Qing, Yuanyuan Li, Xia Gao, Kai Kang, Jason G. Williams, Lingfeng Tong, Juan Liu, et al. “HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer.Nature Communications 11, no. 1 (August 2020): 3978. https://doi.org/10.1038/s41467-020-17818-w.
Xu Q, Li Y, Gao X, Kang K, Williams JG, Tong L, et al. HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer. Nature communications. 2020 Aug;11(1):3978.
Xu, Qing, et al. “HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer.Nature Communications, vol. 11, no. 1, Aug. 2020, p. 3978. Epmc, doi:10.1038/s41467-020-17818-w.
Xu Q, Li Y, Gao X, Kang K, Williams JG, Tong L, Liu J, Ji M, Deterding LJ, Tong X, Locasale JW, Li L, Shats I, Li X. HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer. Nature communications. 2020 Aug;11(1):3978.

Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

August 2020

Volume

11

Issue

1

Start / End Page

3978

Related Subject Headings

  • Transcription, Genetic
  • Sorafenib
  • Mice
  • Methionine
  • Metabolome
  • Metabolic Networks and Pathways
  • Mesoderm
  • Liver Neoplasms
  • Liver
  • Hepatocyte Nuclear Factor 4