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Peer-reviewedCC BYCell death & disease

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

  • Kun Cai1,2
  • Shiyu Chen1,2
  • Guoqing Ma1
  • Wenhao Wu1
  • Songsheng Wang1
  • Baoku Quan1
  • Canhui Jin1
  • Yongqiang Wang3
  • Zhiwei He4,5
  • Tianbao Wang6
6 affiliations
  1. 1Department of Gastrointestinal Surgery, South China Hospital, Medical School, Shenzhen University, Shenzhen, P. R. China.
  2. 2Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, P. R. China.
  3. 3South China Hospital, Medical School, Shenzhen University, Shenzhen, P. R. China. [email protected].
  4. 4Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, P. R. China. [email protected].
  5. 5Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, P. R. China. [email protected].
  6. 6Department of Gastrointestinal Surgery, South China Hospital, Medical School, Shenzhen University, Shenzhen, P. R. China. [email protected].
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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.

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Cite

BibTeXRIS
BibTeX
@article{cai2026targeting,
  title = {{Targeting PSMD14 increases chemotherapeutic sensitivity to gemcitabine by inhibiting the WNT/β-catenin pathway and glycolysis in pancreatic cancer.}},
  author = {Kun Cai and Shiyu Chen and Guoqing Ma and Wenhao Wu and Songsheng Wang and Baoku Quan and Canhui Jin and Yongqiang Wang and Zhiwei He and Tianbao Wang},
  journal = {Cell death \& disease},
  year = {2026},
  month = aug,
  doi = {10.1038/s41419-026-08958-w},
  url = {https://europepmc.org/article/MED/42957640},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Targeting PSMD14 increases chemotherapeutic sensitivity to gemcitabine by inhibiting the WNT/β-catenin pathway and glycolysis in pancreatic cancer.
AU  - Kun Cai
AU  - Shiyu Chen
AU  - Guoqing Ma
AU  - Wenhao Wu
AU  - Songsheng Wang
AU  - Baoku Quan
AU  - Canhui Jin
AU  - Yongqiang Wang
AU  - Zhiwei He
AU  - Tianbao Wang
PY  - 2026
DA  - 2026/08/01
JO  - Cell death & disease
DO  - 10.1038/s41419-026-08958-w
UR  - https://europepmc.org/article/MED/42957640
AB  - 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.
SN  - 2041-4889
ER  -