USP52 promotes clear cell renal carcinoma progression by deubiquitinating and stabilizing CORO6.

Clear cell renal carcinoma (ccRCC) is the most common type of kidney cancer. CORO6 functions as an oncogene in various malignancies, including ccRCC, but the mechanisms regulating its expression, particularly at the post-translational level, remain poorly understood. Ubiquitin-specific proteases (USPs), the largest subfamily of deubiquitinases (DUBs), modulate the ubiquitination of target proteins and play crucial roles in numerous biological processes, such as ccRCC tumorigenesis. In this study, we screened USPs that potentially regulate CORO6 stability and identified USP52 as a key regulator that upregulates CORO6 expression. Bioinformatic analysis revealed that USP52 is overexpressed in ccRCC tissues and is negatively associated with patient prognosis. Similarly, USP52 expression was elevated in ccRCC cell lines, and its knockdown led to decreased CORO6 expression in these cells. In vitro experiments demonstrated that USP52 depletion reduced cell viability and proliferation, induced cell cycle arrest, increased apoptosis, and suppressed the migration and invasion of ccRCC cells. USP52 overexpression promotes the malignant phenotype of ccRCC cells. Mechanistically, USP52 interacts with CORO6, significantly decreasing its K48 ubiquitination and preventing its degradation in ccRCC cells. Notably, overexpression of CORO6 in USP52-deficient ccRCC cells effectively restored their malignant behaviors. Furthermore, using a xenograft mouse model of ccRCC, we found that USP52 deficiency impaired tumor growth in vivo, while CORO6 overexpression rescued the growth of USP52-deficient ccRCC cells. Collectively, these findings reveal that USP52 functions as an oncogene in ccRCC by deubiquitinating and stabilizing CORO6.