In this study, we explored the role of EZH2 and ZIC4 on the physiology and regulation in HCC and found that epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 was an important mechanism in human liver cancer and it would provide a new therapeutic target for the treatment of hepatocellular carcinoma disease. Here, ZIC4 is linked to hepatocellular carcinoma.