USP48 functions as a suppressor of colorectal cancer via SELENBP1 stabilization

Aim: Colorectal Cancer (CRC) is a leading cause of cancer-related death. SELENBP1 is a tumor suppressor in CRC. However, the mechanism regulating the stability of the SELENBP1 protein remains elusive.

Methods: Here, we explored multiple ubiquitin-specific proteases (USPs) that may control SELENBP1 stability. In vitro, USP48 was overexpressed in CRC cell lines to observe its effect on malignant behaviors of cells. The interaction between USP48 and SELENBP1 was investigated using immunoprecipitation.

Results: Our data showed that USP48 exhibits a robust effect in stabilizing SELENBP1. Results of bioinformatics analysis showed that although USP48 expression was variable across datasets, its prognostic signal was consistent, and it was positively correlated with the prognosis of CRC patients. USP48 expression is also decreased in multiple CRC cells, and overexpression of USP48 impaired the malignant behaviors and stemness of HCT-116 and LOVO CRC cells. At the molecular level, USP48 interacts with SELENBP1 in CRC cells. USP48 overexpression substantially decreased the ubiquitination level of SELENBP1 and enhanced its stability. Depletion of SELENBP1 in USP48-overexpressing CRC cells improved their malignant behaviors and stemness, suggesting that SELENBP1 is a key factor in mediating the tumor suppressor function of USP48 in CRC.

Conclusion: Together, these observations deepen our understanding of the post-translational regulation of SELENBP1 and underscore the diagnostic and therapeutic potential of the USP48-SELENBP1 axis in CRC.