AbstractBladder cancer (BC) is the most popular malignant urinary cancer in China. BC has the highest incidence and mortality among all genitourinary system tumors. Although the early-stage BC could be treated with advanced electron flexible systourethroscope, early metastasis of the BC occur frequently and often results in poor prognosis. Recently, we reported that small ubiquitin related modifier (SUMO)-specific protease 2 (SENP2) was downregulated in BC specimen. SENP2 appeared to inhibit migration and invasion of bladder cancer cells in vitro, through suppressing MMP13 in BC cells. However, the exact underlying mechanisms remain unknown. Here, we reported that SENP2 inhibited nuclear translocation of β-catenin, which targeted the promotor of MMP13 to activate MMP13 to enhance BC cell metastasis. WNT ligands induced TBL1/TBLR1 SUMOylation to form complexes with β-catenin to facilitate β-catenin nuclear translocation, which could be efficiently inhibited through suppression of SUMOylation of TBL1/TBLR1. Together, our data suggest that SENP2 inhibits MMP13 expression in BC cells through de-SUMOylation of TBL1/TBLR1, which inhibits nuclear translocation of β-catenin. Thus, SENP2 may be a promising therapeutic target for BC.