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.
Highlights
Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy
Our analysis of The Cancer Genome Atlas (TCGA) human Liver Hepatocellular Carcinoma (LIHC) dataset confirmed that key genes involved in sulfur amino acid (SAA) metabolism, including MAT1A, betaine-homocysteine S-methyltransferase (BHMT), CBS, cystathionine gamma-lyase (CTH), and CDO1, are suppressed in hepatocellular carcinoma (HCC) compared to normal liver (Supplementary Fig. 1a)
HCC patients with low tumor expression of these key SAA enzymes had significantly worse prognosis than those with high expression of these genes (Supplementary Fig. 1b). These data suggest that SAA metabolism is frequently disrupted in liver tumors and this disruption is correlated with patient prognosis
Summary
Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. Our results suggest that the status of HNF4α and SAA metabolism may dictate the sensitivity of liver cancer cells to methionine/cystine restriction and sorafenib treatment.
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