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HNF4? regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer.

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 4? (HNF4?) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4?. Knocking down HNF4? or SAA enzymes in HNF4?-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 HNF4? deficiency in liver cancer cells. Our study identifies HNF4? as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.

SUBMITTER: Xu Q

PROVIDER: S-EPMC7414133 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Xu Qing Q Li Yuanyuan Y Gao Xia X Kang Kai K Williams Jason G JG Tong Lingfeng L Liu Juan J Ji Ming M Deterding Leesa J LJ Tong Xuemei X Locasale Jason W JW Li Leping L Shats Igor I Li Xiaoling X

Nature communications 20200807 1

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) met ...[more]

PMID: 32770044

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Project description:BackgroundIn mammals, the nutritional status experienced during embryonic development shapes key metabolic pathways and influences the health and phenotype of the future individual, a phenomenon known as nutritional programming. In farmed birds as well, the quantity and quality of feed offered to the dam can impact the phenotype of the offspring. We have previously reported that a 38% reduction in the intake of the methyl donor methionine in the diet of 30 female ducks during the growing and laying periods - from 10 to 51 weeks of age - reduced the body weight of their 180 mule ducklings compared to that of 190 ducklings from 30 control females. The maternal dietary methionine restriction also altered the hepatic energy metabolism studied in 30 of their ducklings. Thus, their plasma glucose and triglyceride concentrations were higher while their plasma free fatty acid level was lower than those measured in the plasma of 30 ducklings from the control group. The objective of this new study was to better understand how maternal dietary methionine restriction affected the livers of their newly hatched male and female ducklings by investigating the hepatic expression levels of 100 genes primarily targeting energy metabolism, amino acid transport, oxidative stress, apoptotic activity and susceptibility to liver injury.ResultsSixteen of the genes studied were differentially expressed between the ducklings from the two groups. Maternal dietary methionine restriction affected the mRNA levels of genes involved in different pathways related to energy metabolism such as glycolysis, lipogenesis or electron transport. Moreover, the mRNA levels of the nuclear receptors PPARGC1B, PPARG and RXRA were also affected.ConclusionsOur results show that the 38% reduction in methionine intake in the diet of female ducks during the growing and egg-laying periods impacted the liver transcriptome of their offspring, which may explain the previously observed differences in their liver energy metabolism. These changes in mRNA levels, together with the observed phenotypic data, suggest an early modulation in the establishment of metabolic pathways.

Dataset Information

HNF4? regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer.

Publications

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

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