USP7 overexpression prevents the progression of clear cell renal cell carcinoma by enhancing pyroptosis via TRIP12 deubiquitination.

Ubiquitin-specific protease 7 (USP7) involves in various human cancers due to its capacity for binding and stabilizing specific target proteins through deubiquitylation, but its roles in clear cell renal cell carcinoma (ccRCC) development remains unknown. This study aimed to determine the role of USP7 in the pyroptosis mechanism in ccRCC, thereby providing novel anti-ccRCC strategies. Bioinformatics analysis was conducted to explore the expression of USP7 and TRIP12 in ccRCC patients and their association with patient overall survival. qRT-PCR, western blotting, and ELISA were used to determine the levels of USP7, TRIP12, pyroptosis-related factors. Cell viability, invasion, pyroptosis, and proliferation were evaluated using CCK-8, Transwell, flow cytometry, and immunohistochemistry assays. The direct interaction between USP7 and TRIP12 was validated by co-immunoprecipitation (CO-IP). We found downregulated USP7 in ccRCC tissues, which was related to the shorter patient overall survival (OS). Significantly, USP7 was also decreased in ccRCC cells. oe-USP7 (USP7 overexpression) inhibited ccRCC cell viability, migration, invasion, and enhanced pyroptosis. The caspase-1 specific inhibitor, VX-765, partially abolished the anti-viability, and pro-pyroptosis effects of oe-USP7, indicating USP7 overexpression prevented the malignant phenotype of ccRCC cells by enhancing caspase-1 dependent pyroptosis. Similarly, the shorter patient OS was indicated to be associated with reduced TRIP12 in ccRCC tissues. Besides, oe-USP7 increased TRIP12 expression in ccRCC cells by deubiquitinating TRIP12, while sh-TRIP12 eliminated the biological functions of oe-USP7. The similar effects of oe-USP7 on ccRCC development were found in ccRCC mice. USP7 mediated TRIP12 deubiquitination inhibited ccRCC progression by enhancing pyroptosis.