USP15-mediated stabilization of ZEB1 drives epithelial-mesenchymal transition and metastasis in colorectal cancer

Metastasis is the primary cause of death among patients with colorectal cancer (CRC). Although the deubiquitinating enzyme Ubiquitin-specific peptidase 15 (USP15) has been implicated in the metastatic progression of several malignancies, its role in CRC development and metastasis remains poorly understood. This study aims to investigate the biological function of USP15 in CRC metastasis. USP15 was significantly upregulated in CRC tissues and was found to be associated with an unfavorable patient prognosis. Both in vitro and in vivo experiments demonstrated that USP15 promoted CRC cell proliferation and metastatic potential. USP15 stabilized Zinc finger E-box binding homeobox 1 (ZEB1) by reducing its ubiquitination, enhancing epithelial-mesenchymal transition (EMT), and facilitating CRC progression. Co-immunoprecipitation (Co-IP) assays further verified a direct interaction between USP15 and ZEB1. Ectopic overexpression of ZEB1 effectively rescued the inhibitory effects caused by USP15 depletion. These results identify USP15 as a key regulator of CRC progression by stabilizing ZEB1 and highlight its potential as a therapeutic target for CRC.