Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergizes the anticancer effects of sorafenib in hepatocellular carcinoma

Sorafenib, a multiple-kinase inhibitor, has been widely used as a first-line anticancer drug for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance to sorafenib is frequently observed in clinical applications. Potential non-kinase targets of sorafenib have not been well documented and may provide insights into reversing drug resistance. Herein, we report that sorafenib exerted its anticancer effects by activating metallothionein 1G (MT1G) expression. MT1G served as a novel marker in HCC and correlated well with patient survival. MT1G overexpression suppressed the cellular proliferation, migration, invasion, and tumor formation of HCC, and sensitized cells to sorafenib treatment. However, the disruption of MT1G attenuated sorafenib’s anticancer effects. Mechanistically, sorafenib upregulated MT1G expression via hypomethylation of its promoter region by binding and inhibiting DNA methyltransferase 1 (DNMT1) and increasing its promoter accessibility in HCC cells. The activation of MT1G also inhibited CA9 transcription through the degradation of HIF1a as mediated by KLF4. Our collective data revealed that sorafenib exerted its anticancer effects through epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis in HCC, and that the activation of MT1G might constitute a strategy for reversing sorafenib resistance. 6 mRNA profiles of Huh7 cell lines, including 3 samples treated by DMSO, 3 samples treated by Sorafenib 6 mRNA profiles of Huh7 cell lines, including 3 MT1G over expression sampels, 3 empty vector samples 2 ATAC-seq samples, including 2 samples treated by DMSO, 2 samples treated by Sorafenib