Background <p>Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies worldwide. Ubiquitination is a biological process that regulates the degradation of proteins. Previous studies have indicated that ubiquitin ligase E3C (UBE3C) has procarcinogenic properties in various tumours. Nevertheless, the detailed role of UBE3C in PDAC is still unknown.</p> Methods and results <p>Bioinformatics analyses of UBE3C were performed, and we found that UBE3C expression was increased in PDAC cells and indicates a poorer clinical prognosis. Moreover, a significant positive correlation existed between UBE3C expression and the number of CD4⁺ T cells in the tumour microenvironment (TME) of PDAC. CCK-8, colony formation, EdU and flow cytometry assays indicated that UBE3C knockdown promoted apoptosis and inhibited PDAC cell growth, whereas UBE3C overexpression had the opposite effects. Additionally, UBE3C catalysed p53 ubiquitination and promoted pancreatic carcinogenesis by facilitating p53 degradation. This effect was also confirmed in rescue experiments performed with pifithrin-α (PTF-α, an inhibitor of p53).</p> Conclusions <p>Our results clarify the importance of UBE3C in PDAC and indicate that the UBE3C-p53 axis may be a novel therapeutic target for PDAC.</p> Clinical trial number <p>Not applicable.</p>