【Objective】The aim of this study was to detect the effect and mechanism of EZH1/2 inhibitor UNC1999 on hepatocellular carcinoma cell line SMMC- 7721.【Methods】Two groups including DMSO group（control group）and UNC1999 group were treated with different concentration of DMSO and UNC1999 for different time，respectively，then OD values were detected by using CCK- 8 kit to screen the appropriate action concentration and time of UNC1999. Cell proliferation rate was detected with EdU（5-ethynyl-2-deoxyuridine）Cell Proliferation Kit. The clone formation ability of cell was investigated by clone formation assay. Wound healing assay and transwell assay were used to detect the ability of migration and invasion. Annexin V-FITC/PI double staining assay was performed to detect cell apoptosis. Flow cytometry was used to detect cell cycle. RNA-seq was performed to detect the cell transcriptomics. qRT-PCR was conducted to investigate the related genes，including EZH1，EZH2 and NECTIN4. Western blot was conducted to detect the expression of EZH1 ，EZH2 and H3K27me3. 【Results】 Compared with the control group ，the UNC1999 group showed lower cell proliferation，inhibited ability of migration and invasion（P < 0.05）. In UNC1999 group，G0/1 block occurred in the cell cycle（P<0.05），while cell apoptosis had no significant change（P > 0.05）.【Conclusion】UNC1999 could inhibit HCC by suppressing the expression of EZH1 and EZH2 both in protein level，as well as their function of catalyzing histone methylation. EZH1 and EZH2 play important roles in HCC，which may be potential targets for HCC treatment. UNC1999 could significantly promote the expression of NECTIN4 isoform which has been reported to be associated with the response to anti-cancer drug ，suggesting that the combination of EZH1/2 inhibitor and anti-cancer drug may exert greater effect of inhibiting HCC. This can provide a new idea for clinical drug treatment of liver cancer.