2. Academic Validation
  3. Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC

Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC

  • Cell Death Dis. 2022 Nov 10;13(11):951. doi: 10.1038/s41419-022-05341-3.
Longhao Wang # 1 2,  Tao Hu # 3,  Zhibo Shen 1 2,  Yuanyuan Zheng 1 2,  Qishun Geng 1 2,  Lifeng Li 1,  Beibei Sha 3,  Miaomiao Li 3,  Yaxin Sun 3,  Yongjun Guo 4,  Wenhua Xue 2,  Dan Xuan 5,  Ping Chen 6,  Jie Zhao 7 8
Affiliations

Affiliations

  • 1 Internet Medical and System, Applications of National Engineering Laboratory, The First Afliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
  • 2 Department of Pharmacy, The First Afliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
  • 3 Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 4 The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No 127, Dongming Road, Zhengzhou, Henan, 450008, China.
  • 5 Experimental animal center of Zhengzhou University, Zhengzhou, China.
  • 6 Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. zzdx_chenping@zzu.edu.cn.
  • 7 Internet Medical and System, Applications of National Engineering Laboratory, The First Afliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. zhaojie@zzu.edu.cn.
  • 8 Department of Pharmacy, The First Afliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. zhaojie@zzu.edu.cn.
  • # Contributed equally.
PMID: 36357365 DOI: 10.1038/s41419-022-05341-3
Abstract

The deubiquitinating Enzyme USP1 (Ubiquitin-Specific Protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 Inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and Caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect Autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent Apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective Autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, Apoptosis, and Autophagy in ML-323-treated HCC cells. In addition, blocking Autophagy using the AMPK Inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.

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