Int J Biol Sci 2021; 17(13):3634-3645. doi:10.7150/ijbs.61795 This issue

Research Paper

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer

Ting Sun1✉, Hui Peng1*, Wenhao Mao2*, Liwei Ma1, Hongyang Liu3, Jia Mai4, Lin Jiao5

1. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
2. Department of Clinical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
3. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
4. Department of Laboratory Medicine, West China Second Hospital, Sichuan University, Chengdu 610041, China.
5. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
*These authors contributed equally to this work.

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Citation:
Sun T, Peng H, Mao W, Ma L, Liu H, Mai J, Jiao L. Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer. Int J Biol Sci 2021; 17(13):3634-3645. doi:10.7150/ijbs.61795. Available from https://www.ijbs.com/v17p3634.htm

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Abstract

Graphic abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

Keywords: pancreatic cancer, YAP, autophagy, Atg5, verteporfin