Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, 518020, China.
Department of Science and Education, The First Affiliated Hospital of Guiyang University of Chinese Medicine, Guiyang, 550001, Guizhou, China.
Cell Death Dis. 2020 Oct 23;11(10):906. doi: 10.1038/s41419-020-03109-1.
Inactivation of tumor suppressor gene played critical roles in the development and progression of human hepatocellular carcinoma (HCC). Zic family member 4 (ZIC4) is transcription factor and plays an important role in the developmental process. However, the expression and biological role of ZIC4 in HCC is poorly understood. Here, bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database revealed an aberrant hypermethylation of ZIC4 in HCC. ZIC4 is frequently hypermethylated in promoter region and down expressed in HCC cells and tissues. Functionally, ZIC4 inhibition facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, ZIC4 overexpression reduced proliferation and invasiveness of HCC cells. In addition, ZIC4 inhibition rescued the antitumor effect induced by enhancer of zeste homolog 2 (EZH2) knockdown or EZH2 inhibitor. Mechanistically, EZH2 knockdown or EZH2 inhibitor reduced the enrichment of EZH2 and H3K27me3 in ZIC4 promoter region and leading to the upregulation of ZIC4. Altogether, these data indicate that epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in HCC and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.
肿瘤抑制基因失活在人类肝细胞癌 (HCC) 的发生和发展中起着关键作用。锌指蛋白家族成员 4 (ZIC4) 是一种转录因子，在发育过程中发挥重要作用。然而，ZIC4 在 HCC 中的表达和生物学作用仍知之甚少。本研究基于癌症基因组图谱 (TCGA) 数据库的生物信息学分析揭示了 HCC 中 ZIC4 的异常高甲基化。ZIC4 在 HCC 细胞和组织中常因启动子区域的高甲基化而表达下调。功能上，ZIC4 的抑制作用促进了 HCC 细胞的体外和体内增殖、迁移、侵袭和上皮-间充质转化 (EMT)。相反，ZIC4 的过表达降低了 HCC 细胞的增殖和侵袭能力。此外，ZIC4 的抑制作用挽救了增强子结合蛋白 2 (EZH2) 敲低或 EZH2 抑制剂诱导的抗肿瘤作用。机制上，EZH2 敲低或 EZH2 抑制剂降低了 ZIC4 启动子区域的 EZH2 和 H3K27me3 的富集，导致 ZIC4 的上调。总之，这些数据表明，EZH2 介导的 H3K27me3 对 ZIC4 的表观遗传沉默是 HCC 的一个重要机制，并为治疗肝细胞癌疾病提供了一个新的治疗靶点。
