UBE2W promotes pancreatic cancer progression through regulating K63-linked ubiquitination of p53

Ubiquitin-conjugating enzyme E2W (UBE2W), a member of the ubiquitin-conjugating enzyme family, is highly expressed in pancreatic cancer (PC). However, the biological function of UBE2W in cancer, particularly in human PC, remains poorly understood. This study aimed to elucidate the molecular mechanism by which UBE2W regulates the initiation and progression of PC. Integrating multiple databases and validating with clinical samples, the study identified that UBE2W is significantly overexpressed in PC tissues. High UBE2W expression is closely associated with shortened overall survival, disease-specific survival, and disease-free survival in patients. In vitro and in vivo functional experiments demonstrated that UBE2W overexpression promotes the proliferation and migration of PC cells while inhibiting apoptosis. Conversely, UBE2W knockdown significantly reduces cell viability, induces apoptosis, and suppresses tumor growth in vivo. Mechanistically, UBE2W mediates K63-linked ubiquitination of p53, regulates p53 subcellular localization, and thereby impairs p53-mediated DNA damage repair and apoptotic pathways. Collectively, UBE2W inhibits the tumor-suppressive function of p53 and promotes PC progression through the aforementioned mechanism. Targeting the UBE2W-p53 axis provides a novel therapeutic strategy for PC, and the development of related inhibitors holds promise for improving patient prognosis.