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

Wei，Tianzi1,3; Lin，Risheng4; Fu，Xing4; Lu，Yi4,5; Zhang，Weiwen2; Li，Zhengxuan1; Zhang，Jian4,5; Wang，Hao1,2

2022-06-01

10.1016/j.phrs.2022.106244

PHARMACOLOGICAL RESEARCH   影响因子和分区

1043-6618

1096-1186

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.

CA9 DNMT1 HCC HIF1A KLF4 MT1G Sorafenib

SCI

英语

第一 ; 通讯

Shenzhen Science and Technology Innovation Commission Project["JCYJ20180302174235893","JCYJ201 90809161811237","JCYJ2021032410424040","JCYJ201704121529437 94","JCYJ20170412154619484"] ; NSFC Project[81972766,82173336,81972420,81773146] ; Project of Department of education of Guangdong province[2021KQNCX074] ; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research[2017B030301018]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000806810200003

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85130358699

Scopus

1.Department of Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China
2.Shenzhen University General Hospital,Shenzhen University,Shenzhen,Guangdong,518061,China
3.School of Biomedical Sciences,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong
4.School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China
5.Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen,Guangdong,518055,China

Wei，Tianzi,Lin，Risheng,Fu，Xing,et al. Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergises the anticancer effects of sorafenib in hepatocellular carcinoma[J]. PHARMACOLOGICAL RESEARCH,2022,180.

Wei，Tianzi.,Lin，Risheng.,Fu，Xing.,Lu，Yi.,Zhang，Weiwen.,...&Wang，Hao.(2022).Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergises the anticancer effects of sorafenib in hepatocellular carcinoma.PHARMACOLOGICAL RESEARCH,180.

Wei，Tianzi,et al."Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergises the anticancer effects of sorafenib in hepatocellular carcinoma".PHARMACOLOGICAL RESEARCH 180(2022).