We recently report that the expression of polycomb chromobox 4 (Cbx4) is significantly correlated with the overall survival of a great cohort of hepatocellular carcinoma (HCC) patients and it enhances hypoxia-induced vascular endothelial growth factor (VEGF) expression and angiogenesis in HCC cells through enhancing sumoylation of hypoxia inducible factor-1alpha (HIF-1α). Here we continue to investigate the potential effects of Cbx4 on the migration and metastasis of the metastatic HCC cell line MHCC97L. Our results show that Cbx4 overexpression in the cell line increases the in vitro vessel formation of vascular endothelial cells in its SUMO interaction motifs-dependent manner, and promotes the in vitro migration of the cancer cell, which can be effectively abrogated by anti-VEGF antibody. Although Cbx4 expression does not impact the in vitro growth of MHCC97L cells, it still promotes the progression and metastasis of orthotopically transplanted tumors in nude mice. These results further support the role of Cbx4 as a SUMO E3 ligase in the progression and metastasis of HCC.