EZH2, a histone methyltransferase, has been shown to involve in cancer development and progression via epigenetic regulation of tumor suppressor microRNAs, whereas BMI1, a driver of hepatocellular carcinoma (HCC), is a downstream target of these microRNAs. However, it remains unclear whether EZH2 can epigenetically regulate microRNA expression to modulate BMI1-dependent hepatocarcinogenesis. Here, we established that high EZH2 expression correlated with enhanced tumor size, elevated metastasis, increased relapse, and poor prognosis in HCC patients. Further clinical studies revealed that EZH2 overexpression was positively correlated to its gene copy number gain/amplification in HCC. Mechanistically, EZH2 epigenetically suppressed miR-200c expression both in vitro and in vivo, and more importantly, miR-200c post-transcriptionally regulated BMI1 expression by binding to the 3′-UTR region of its mRNA. Furthermore, miR-200c overexpression inhibits the growth of HCC cells in vivo. Silencing miR-200c rescued the tumorigenicity of EZH2-depleted HCC cells, whereas knocking down BMI1 reduced the promoting effect of miR-200c depletion on HCC cell migration. Finally, combination treatment of EZH2 and BMI1 inhibitors further inhibited the viability of HCC cells compared with the cells treated with EZH2 or BMI1 inhibitor alone. Our findings demonstrated that alteration of EZH2 gene copy number status induced BMI1-mediated hepatocarcinogenesis via epigenetically silencing miR-200c, providing novel therapeutic targets for HCC treatment.

EZH2是一种组蛋白甲基转移酶，已被证明通过表观遗传调控肿瘤抑制microRNA参与癌症的发展和进程，而肝细胞癌（HCC）的驱动者BMI1是这些microRNA的下游靶标。但是，目前尚不清楚EZH2是否可以表观遗传调控microRNA表达，以调节BMI1依赖性肝癌发生。在这里，我们建立了高EZH2表达与HCC患者的肿瘤大小增加，转移升高，复发增加和预后不良相关。进一步的临床研究表明，EZH2过表达与其在肝癌中的基因拷贝数增加/扩增呈正相关。从机理上讲，EZH2从表观遗传学角度在体外和体内均抑制了miR-200c的表达，更重要的是，miR-200c通过与其mRNA的3'-UTR区结合来转录后调节BMI1表达。此外，miR-200c过表达在体内抑制HCC细胞的生长。沉默miR-200c挽救了EZH2缺失的HCC细胞的致瘤性，而敲低BMI1则降低了miR-200c耗尽对HCC细胞迁移的促进作用。最后，与单独用EZH2或BMI1抑制剂处理的细胞相比，EZH2和BMI1抑制剂的联合处理进一步抑制了HCC细胞的活力。我们的发现表明，EZH2基因拷贝数状态的改变通过表观遗传沉默miR-200c诱导BMI1介导的肝癌发生，为HCC治疗提供了新的治疗靶点。miR-200c过表达在体内抑制HCC细胞的生长。沉默miR-200c挽救了EZH2缺失的HCC细胞的致瘤性，而敲低BMI1则降低了miR-200c耗尽对HCC细胞迁移的促进作用。最后，与单独用EZH2或BMI1抑制剂处理的细胞相比，EZH2和BMI1抑制剂的联合处理进一步抑制了HCC细胞的活力。我们的发现表明，EZH2基因拷贝数状态的改变通过表观遗传沉默miR-200c诱导BMI1介导的肝癌发生，为HCC治疗提供了新的治疗靶点。miR-200c过表达在体内抑制HCC细胞的生长。沉默miR-200c挽救了EZH2缺失的HCC细胞的致瘤性，而敲低BMI1则降低了miR-200c耗尽对HCC细胞迁移的促进作用。最后，与单独用EZH2或BMI1抑制剂处理的细胞相比，EZH2和BMI1抑制剂的联合处理进一步抑制了HCC细胞的活力。我们的发现表明，EZH2基因拷贝数状态的改变通过表观遗传沉默miR-200c诱导BMI1介导的肝癌发生，为HCC治疗提供了新的治疗靶点。与单独使用EZH2或BMI1抑制剂处理的细胞相比，EZH2和BMI1抑制剂的联合处理进一步抑制了HCC细胞的活力。我们的发现表明，EZH2基因拷贝数状态的改变通过表观遗传沉默miR-200c诱导BMI1介导的肝癌发生，为HCC治疗提供了新的治疗靶点。与单独使用EZH2或BMI1抑制剂处理的细胞相比，EZH2和BMI1抑制剂的联合处理进一步抑制了HCC细胞的活力。我们的发现表明，EZH2基因拷贝数状态的改变通过表观遗传沉默miR-200c诱导BMI1介导的肝癌发生，为HCC治疗提供了新的治疗靶点。