EZH2-mediated epigenetic silencing of ZIC4 in hepatocellular carcinoma

Abstract Background: The present study aimed to explore the role of ZIC4 in human liver cancer.Methods: Illumina450 genome-wide methylation data was downloaded from The Cancer Genome Atlas for 50 available liver tumor/surrounding pairs. Wound healing test, colony formation and flow cytometry assay were utilized to analyze cell migration, survival and apoptosis. The effects of EZH2 and ZIC4 on tumor growth were also investigated through in vivo xenograft and orthotopic implantation experiments. Results: ZIC4 was hypermethylated in liver cancer tissues and cell lines. EZH2 knockdown and DZNep mediated H3K27me3 contributes to ZIC4 expression. The antitumor effect of EZH2 knockdown on hepatocellular carcinoma growth, metastasis and epithelial-mesenchymal transition progression in vitro were rescued by sh-ZIC4. Downregulation of ZIC4 also rescued the antitumor effect of DZNep in vivo.Conclusions: Epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in human liver cancer and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.