Wei Tianzi, Lin Risheng, Fu Xing, Lu Yi, Zhang Weiwen, Li Zhengxuan, Zhang Jian, Wang Hao
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.
School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
Pharmacol Res. 2022 Jun;180:106244. doi: 10.1016/j.phrs.2022.106244. Epub 2022 May 9.
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.
索拉非尼是一种多激酶抑制剂，已被广泛用作晚期肝细胞癌（HCC）的一线抗癌药物。然而，在临床应用中经常观察到对索拉非尼产生耐药性。索拉非尼潜在的非激酶靶点尚未得到充分记录，可能为逆转耐药性和提高药物疗效提供思路。在此，我们报告索拉非尼通过激活金属硫蛋白1G（MT1G）的表达发挥其抗癌作用。MT1G是HCC中的一种新型标志物，与患者生存率密切相关。MT1G过表达抑制了HCC的细胞增殖、迁移、侵袭和肿瘤形成，并使细胞对索拉非尼治疗敏感。然而，MT1G的破坏减弱了索拉非尼的抗癌作用。机制上，索拉非尼通过结合并抑制DNA甲基转移酶1（DNMT1），使其启动子区域去甲基化，并增加其在HCC细胞中的启动子可及性，从而上调MT1G的表达。MT1G的激活还通过KLF4介导的对HIF1A的抑制来抑制CA9转录。我们的总体数据表明，索拉非尼通过对HCC中DNMT1/MT1G/KLF4/CA9轴的表观遗传调控发挥其抗癌作用，MT1G的激活可能构成一种增强索拉非尼抑制HCC细胞作用的策略。
