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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • August 7, 2020

Published In

Volume / Issue

  • 11 / 1

Start / End Page

  • 3978 -

PubMed ID

  • 32770044

Pubmed Central ID

  • 32770044

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-020-17818-w

Language

  • eng

Conference Location

  • England