Ubiquitin-specific protease 48 drives malignant progression of colorectal cancer by suppressing autophagy through stabilizing sequestosome 1.

Colorectal cancer (CRC) is the third malignant tumor in incidence rate and the second leading cause of cancer death worldwide. The progression of CRC is associated with both autophagy and ubiquitin-specific proteases (USPs). While USPs have been shown to regulate autophagy, their specific involvement in CRC autophagy remains largely unexplored. Herein, through the analysis of autophagy-related protein expression levels and proteomics, we found that high expression of USP48 was closely related to the inhibition of autophagy in CRC. And further analysis of CRC tissues showed that USP48 served as an independent risk factor for CRC patient prognosis. In vitro, we observed that USP48 significantly enhanced the proliferative, migration and invasion capacities of CRC cells. In vivo experiments showed that USP48 knockdown significantly inhibited the growth of subcutaneous tumors in nude mice, and the deletion of USP48 in intestinal epithelial cells reduced the number of intestinal tumors and mortality rate of mice. Mechanistically, USP48 was found to interact with the autophagy substrate protein sequestosome 1 (SQSTM1) and induce its deubiquitination at K420. This process inhibited autophagy, consequently maintaining the protein stability of SQSTM1. Rescue experiments demonstrated that SQSTM1 was the key target for USP48 to inhibit autophagy and promote CRC progression. Based on these findings, we constructed a tetrahedral DNA nanomaterial loaded with USP48 small interfering RNA (siRNA), which could effectively inhibited the progression of CRC in vivo while exhibiting excellent biocompatibility. In summary, our findings highlighted the role of USP48 in promoting CRC progression via the stabilization of SQSTM1, which leads to the suppression of autophagy. Thus, USP48 may be a potential therapeutic target for CRC.