USP15 Promotes Pancreatic Cancer Progression and Cisplatin Resistance By Activating DNA Damage Repair

ABSTRACT Cisplatin (DDP) is a key chemotherapeutic agent for pancreatic cancer (PC), but its efficacy is often limited by the development of DNA damage repair (DDR)‐mediated resistance. Ubiquitin‐specific peptidase 15 (USP15) is known to activate DDR pathways; however, its specific role and clinical relevance in PC remain poorly understood. We analyzed USP15 expression and its clinical significance using public databases, tissue microarrays, and cell lines through RT‐qPCR, Western blot, and immunohistochemistry. The effect of USP15 on DDP resistance was evaluated using colony formation and flow cytometry assays. Protein interaction between USP15 and POLE3 was confirmed by Co‐IP. DNA damage levels were assessed via immunofluorescence staining, neutral comet assays, and host cell reactivation. Both loss‐of‐function and gain‐of‐function studies of USP15 were conducted in a mouse xenograft model. We found that USP15 was significantly upregulated in PC tissues and correlated with poor patient prognosis. Overexpression of USP15 enhanced DDP resistance in PC cells in vitro and in vivo. Enrichment analysis indicated a strong association between USP15 expression and DDR‐related genes. Mechanistically, USP15 was found to bind to POLE3 and suppress its ubiquitination‐dependent degradation, thereby facilitating DDP‐induced DNA damage repair. Our findings highlight the upregulation and prognostic value of USP15 in PC, and uncover its role in promoting DDR‐mediated DDP resistance through stabilization of POLE3.