2. Academic Validation
  3. Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergises the anticancer effects of sorafenib in hepatocellular carcinoma

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

  • Pharmacol Res. 2022 Jun;180:106244. doi: 10.1016/j.phrs.2022.106244.
Tianzi Wei 1,  Risheng Lin 2,  Xing Fu 2,  Yi Lu 3,  Weiwen Zhang 4,  Zhengxuan Li 5,  Jian Zhang 6,  Hao Wang 7
Affiliations

Affiliations

  • 1 Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 2 School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
  • 3 School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen 518055, Guangdong, China.
  • 4 Shenzhen University General Hospital, Shenzhen University, Shenzhen 518061, Guangdong, China.
  • 5 Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
  • 6 School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen 518055, Guangdong, China. Electronic address: zhangjian@sustech.edu.cn.
  • 7 Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China; Shenzhen University General Hospital, Shenzhen University, Shenzhen 518061, Guangdong, China. Electronic address: haowang0806@szu.edu.cn.
PMID: 35550167 DOI: 10.1016/j.phrs.2022.106244
Abstract

Sorafenib, a multikinase 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 nonkinase targets of sorafenib have not been well documented and may provide insights into reversing drug resistance and enhancing drug efficacy. Herein, we report that sorafenib exerts its Anticancer effects by activating metallothionein 1 G (MT1G) expression. MT1G is a novel marker in HCC that correlates well with patient survival. MT1G overexpression suppressed the cellular proliferation, migration, invasion, and tumour formation of HCC and sensitised cells to sorafenib treatment. However, the disruption of MT1G attenuated the Anticancer effects of sorafenib. 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. Activation of MT1G also inhibited CA9 transcription through the suppression of HIF1A as mediated by KLF4. Our collective data revealed that sorafenib exerts its Anticancer effects through epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis in HCC and the activation of MT1G might constitute a strategy for enhancing the effect of sorafenib to suppress HCC cells.

Keywords

CA9; DNMT1; HCC; HIF1A; KLF4; MT1G; Sorafenib.

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