UBE2C promotes pancreatic tumorigenesis by KRAS stabilization via APC/CCDH1-mediated WDR76 degradation

Bioinformatics-based association study revealed a strong positive correlation between UBE2C, an E2 ubiquitin-conjugating enzyme, and pancreatic cancer and patient survival. However, whether and how UBE2C plays a causal role in pancreatic tumorigenesis remains elusive. Here, we report that UBE2C functions as a promoter in this process. Specifically, both the mRNA and protein levels of UBE2C are upregulated in pancreatic ductal adenocarcinoma (PDAC), and its levels significantly correlate with poor prognosis. In cell culture models, UBE2C knockdown inhibits the proliferation, survival, migration, and invasion of pancreatic cancer cells, while its overexpression promotes these processes. In in vivo mouse models, Ube2c deletion suppresses pancreatic tumorigenesis and metastasis, driven by Kras^G12D and Kras^G12D;p53^−/−, respectively, thereby significantly extending the lifespan of the mice. Mechanistically, WDR76 couples with CUL1 E3 ligase, rather than CUL4, to promote the degradation of both wild-type and mutant KRAS, thus destabilizing KRAS. In contrast, UBE2C cooperates with APC/C^CDH1 E3 ligase to degrade WDR76 in a KEN-box motif-dependent manner, leading to KRAS accumulation and activation of the MAPK signaling pathway, which drives pancreatic tumorigenesis. Notably, WDR76 levels in pancreatic tissues of Kras^G12D-driven mice decrease as PDAC progresses, while the levels of KRAS^G12D and UBE2C increase. Furthermore, simultaneous WDR76 knockdown via adeno-associated virus (AAV) injection into the pancreatic duct fully rescues RAS/ERK inactivation and PDAC suppression caused by Ube2c deletion, demonstrating a causal role of the UBE2C-WDR76 axis. Collectively, these findings suggest that the UBE2C-WDR76 axis may represent a promising therapeutic target for the treatment of KRAS-driven pancreatic cancer.