Hemangioma (HA) is a neoplastic disease derived from vascular endothelial cells. Recently, SASH1 has been identified as a tumor suppressor gene. The purpose of this study was to investigate the role and regulatory mechanism of SASH1 in HA. RT-PCR and Western blot were used to detect the expressions of SASH1, TRAF6 and EZH2 in HA tissues and cell lines. CCK-8, cell cycle, apoptosis, wound healing and Transwell assays were performed to evaluate the effects of SASH1 and EZH2 exerted on HA cells. The immunoprecipitation and ubiquitination assays validated the regulation of SASH1 on TRAF6 and EZH2 ubiquitination. The results showed that SASH1 and EZH2 were highly expressed in HA tissues and cell lines, while TRAF6 was downregulated. SASH1 knockdown inhibited HemECs proliferation, migration, as well as invasion, and induced G0/G1 cell cycle arrest and apoptosis, while EZH2 overexpression reversed these effects. Interestingly, the knockdown of SASH1 enhanced TRAF6 expression but suppressed EZH2 expression in HemECs. And the ubiquitination of EZH2 and TRAF6 was regulated by SASH1. Generally, SASH1 knockdown inhibited TRAF6 ubiquitination to destabilize EZH2. SASH1 may serve as a novel therapeutic target during HA progression.