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  2. USP1 promotes pancreatic cancer progression and autophagy by deubiquitinating ATG14

USP1 promotes pancreatic cancer progression and autophagy by deubiquitinating ATG14

  • J Biol Chem. 2025 Jan 13;301(3):108190. doi: 10.1016/j.jbc.2025.108190.
Leilei Li 1 Zhili Fan 1 Mengfei Liu 1 Hao Dong 1 Jing Li 1 Yu Li 1 Zan Song 1 Ying Liu 1 Zhicheng Zhang 1 Xinyu Gu 1 Tao Zhang 2
Affiliations

Affiliations

  • 1 Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2 Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, Guangxi, China. Electronic address: zhangtao@sdu.edu.cn.
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis, high mortality, and limited therapeutic strategy. Autophagy is hyperactivated in PDAC, and targeting Autophagy is emerging as a promising therapeutic strategy. The dysfunction of Deubiquitinase ubiquitin-specific peptidase 1 (USP1) results in tumorigenesis and chemotherapy resistance. However, little is known about how USP1 regulates Autophagy and its mechanism in tumor progression and drug sensitivity in PDAC. In this study, we found USP1 elevated in pancreatic Cancer and USP1 expression inversely correlated with overall survival. USP1 depletion inhibited cell proliferation, epithelial-mesenchymal transition, and migration in PDAC cells. Interestingly, USP1 knockdown or inhibition reduced Autophagy initiation and Autophagy flux. By screening of interacting protein using coimmunoprecipitation, we identified that USP1 interacted with ATG14 (autophagy-related gene 14) protein, acting as a core component in Autophagy initiation. Furthermore, USP1 overexpression deubiquitinated and enhanced ATG14 protein stability by reduced binding ubiquitin levels, whereas USP1 inhibition promoted its proteasome-dependent degradation. Notably, USP1 depletion or a novel USP1 Inhibitor I-138 dramatically delayed tumor growth in xenograft model. USP1 Inhibitor synergistically enhanced the Anticancer efficiency of cisplatin in PDAC cells. Collectively, our study identifies USP1 as the first Deubiquitinase in the modulation of ATG14 deubiquitination and unveils a regulatory role for USP1 in Autophagy and PDAC progression. Targeting USP1 using a selective inhibitor I-138 may provide an effective strategy for chemotherapy treatment and combating drug resistance in autophagy-activated pancreatic Cancer.

Keywords

ATG14; USP1; autophagy; cisplatin sensitivity; pancreatic ductal adenocarcinoma.

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