USP32 stabilizes SEMA4C to promote malignant behavior of colon cancer cells

Colorectal cancer (CRC) is a prevalent and deadly malignancy. SEMA4C has been found to promote CRC progression, although the regulatory mechanisms behind SEMA4C expression in CRC tissues remain elusive. In this study, we examined 40 ubiquitin-specific proteases (USPs) that may influence SEMA4C stability and identified USP32 as a potent stabilizer. Through bioinformatics analysis, we discovered that USP32 mRNA expression is elevated in CRC tissues. Suppressing USP32 led to decreased cell viability, cell cycle arrest, reduced migration and invasion capabilities, and lower levels of proteins associated with epithelial-to-mesenchymal transition (EMT). USP32 directly interacts with SEMA4C in CRC cells, and its knockdown heightened SEMA4C ubiquitination and accelerated its degradation. Moreover, USP32 enhances the protein stability of SEMA4C by regulating its K48 ubiquitination. Overexpressing SEMA4C strengthened the weakened malignant behaviors of USP32-deficient CRC cells. These results indicate that USP32 acts as an oncogene in CRC by stabilizing SEMA4C, highlighting a new mechanism in CRC pathogenesis and suggesting USP32 as a novel potential therapeutic target for CRC treatment.