Department of Laboratory Medicine, Department of Biochemistry and Molecular Biology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Department of Laboratory Medicine, Department of Biochemistry and Molecular Biology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Exp Cell Res. 2019 Jun 1;379(1):1-10. doi: 10.1016/j.yexcr.2019.03.017. Epub 2019 Mar 18.
Zinc-figure protein 217 (ZNF217) is a C2H2 zinc finger transcription factor that works as a pivotal effector stimulating embryonic immortalization as well as oncogenicity during multiple cancer processes. Nevertheless, the expression of ZNF217 in hepatocellular carcinoma (HCC) and the underlying specific molecular mechanisms remains elusive. In the present study, we aimed to explore the potential role of ZNF217 in HCC cell proliferation and invasion, as well as the underlying mechanism. Here, we demonstrated that the expression of ZNF217 was higher in HCC patients and indicated worse overall survival times, which was confirmed by Oncomine datasets and The Cancer Genome Atlas (TCGA) HCC cohorts. Further research discovered that knockdown of ZNF217 inhibited the proliferation of HCC cells in vitro and in vivo. Enforced expression of ZNF217 could promote Epithelial-mesenchymal transition and thus the invasion of HCC cells. Mechanistically, we identified ZNF217 interacted with LSD1 in vivo and in vitro. Knockdown of ZNF217 was accompanied by a parallel increase in di-methyl histone 3 lysine4 levels on CDH1 promoter, which indicated ZNF217 could recruit LSD1 to affect CDH1 epigenetic expression from transcription level. Of note, bioinformatics analyses, a dual luciferase reporter assay, RT-qPCR and western blot analysis demonstrated that microRNA-101 (miR-101), a well-known tumor suppressor in HCC, acted as a negative regulator of ZNF217. The inhibition of HCC progression by miR-101 was counteracted by ZNF217 overexpression. Taken together, our study presents the regulation mechanism of miR-101/ZNF217/CDH1 axis for the first time and provides new evidences of ZNF217 as a potential therapeutic target for HCC patients.
锌指蛋白 217（ZNF217）是一种 C2H2 锌指转录因子，作为一种关键效应因子，在多种癌症过程中刺激胚胎永生化和致癌性。然而，ZNF217 在肝细胞癌（HCC）中的表达及其潜在的特定分子机制仍不清楚。在本研究中，我们旨在探讨 ZNF217 在 HCC 细胞增殖和侵袭中的潜在作用及其潜在机制。结果表明，ZNF217 在 HCC 患者中的表达水平较高，且总生存期较差，这一点得到了 Oncomine 数据集和癌症基因组图谱（TCGA）HCC 队列的证实。进一步研究发现，ZNF217 的敲低抑制了 HCC 细胞的体外和体内增殖。ZNF217 的过表达可促进上皮-间充质转化，从而促进 HCC 细胞的侵袭。机制上，我们在体内和体外鉴定了 ZNF217 与 LSD1 相互作用。ZNF217 的敲低伴随着 CDH1 启动子上二甲基组蛋白 3 赖氨酸 4 水平的平行增加，表明 ZNF217 可以募集 LSD1 从转录水平影响 CDH1 的表观遗传表达。值得注意的是，生物信息学分析、双荧光素酶报告基因检测、RT-qPCR 和 Western blot 分析表明，miR-101（一种在 HCC 中已知的肿瘤抑制因子）作为 ZNF217 的负调节剂。miR-101 对 HCC 进展的抑制作用被 ZNF217 的过表达所抵消。综上所述，本研究首次提出了 miR-101/ZNF217/CDH1 轴的调控机制，为 ZNF217 作为 HCC 患者潜在治疗靶点提供了新的证据。
