The SUMO specific peptidase SENP3 promotes papillary thyroid cancer progression by deSUMOylation of SETDB1 and regulating GLI2 transcription.

SUMO-specific protease 3 (SENP3) was reported to be dysregulated in osteosarcoma and ovarian cancer. However, the role of SENP3 in carcinogenesis of papillary thyroid cancer (PTC) has not been defined. Herein, we found that the expression of SENP3 protein was upregulated in PTC tissues and cell lines. Then, a PTC cell line, K-1 cells were transfected with SENP3 overexpression plasmid (pcDNA-SENP3) or small interfering RNA targeting SENP3 (SENP3 siRNA). We found that SENP3 overexpression facilitated cell proliferation and invasion, induced cell cycle arrest at G0/G1 phase and inhibited apoptosis in PTC cells, whereas SENP3 knockdown showed the opposite results. We further found that SET domain bifurcated 1 (SETDB1) can be regulated by SENP3-dependent deSUMOylation. Furthermore, SUMOylation of SETDB1 promoted SETDB1 to form a complex with MBD1-containing chromatin-associated factor 1 (MCAF1), and in turn to occupy the promoter locus of GLI family zinc finger 2 (GLI2) gene to suppress GLI2 expression through trimethylation of histone H3 Lys9 (H3K9me3). Then rescue experiments showed that GLI2 overexpression reversed the effects of SENP3 silencing on K-1 cell functions. The PI3K/AKT pathway inhibitor XL147 suppressed the effects of SENP3 overexpression on K-1 cell behaviors. Additionally, SENP3 knockdown significantly inhibited the xenograft tumor growth of PTC in vivo. This study revealed that SENP3 promoted PTC progression in vitro and in vivo by deSUMOylating SETDB1, thereby relieving SETDB1-mediated repression of GLI2 H3K9 trimethylation, which may provide a potential therapeutic target for PTC.