Targeting PSMD14 increases chemotherapeutic sensitivity to gemcitabine by inhibiting the WNT/β-catenin pathway and glycolysis in pancreatic cancer

Abstract Chemotherapy resistance is one of the important reasons for the low 5-year survival rate of patients with pancreatic cancer. Elucidating the mechanism of chemotherapy resistance is an important breakthrough direction for improving the prognosis. Here, PSMD14, a deubiquitinating enzyme frequently overexpressed in human pancreatic cancer, was demonstrated to mediate chemoresistance principally by activating the WNT/β-catenin pathway. Mechanistically, PSMD14 activated the WNT/β-catenin pathway by removing the K63-linked ubiquitination of DVL1 and promoting its translocation from the cytoplasm to the membrane, consequently facilitating the aerobic glycolysis and contributing to the chemoresistance of pancreatic cancer cells. Furthermore, activation of the WNT/β-catenin pathway promoted the transcription of PSMD14, and the PSMD14 inhibitor capzimin improved the sensitivity of pancreatic cancer cells to gemcitabine in cells, organoids, and mouse models. In conclusion, PSMD14 plays a critical role in regulating the activity of WNT/β-catenin and the sensitivity of pancreatic cancer to gemcitabine, suggesting that PSMD14 appears to be a promising therapeutic target for pancreatic cancer.