Prolonged methionine restriction induces liver cancer persistence

ABSTRACT: Methionine restriction (MR) has been shown to inhibit cancer cell growth and enhance cancer therapy. However, its long-term impact on cancer progression remains unknown. Here we report that prolonged methionine restriction in epithelial human liver cancer cells leads to the formation of drug-tolerant persisters. Epithelial human HCC cells, such as HepG2 and Huh7 cells, could survive prolonged methionine restriction. The surviving cells display typical characteristics of persistent cancer cells, including slow proliferation, diminished protein synthesis, gain of mesenchymal features, and resistance to chemotherapy. RNA-seq analysis reveals that MR persisters have increased expression of genes mediating cell migration, inflammation, and stress response, yet reduced abundance of genes involved in cell cycle regulation, metabolism, detoxification, and translation. These transformations closely resemble those previously observed in liver cancer cells knocked down hepatocyte nuclear factor 4 (HNF4), suggesting that the formation of persistent liver cancer cells may be coupled with diminished HNF4 activity. In support of this possibility, genes altered in MR persisters significantly overlapped with those changed by HNF4 knockdown. Moreover, about 40% of downregulated genes shared by both HepG2 and Huh7 MR persister cells have been previously identified as HNF4 target genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314964 | GEO | 2026/09/19

REPOSITORIES: GEO