2. Academic Validation
  3. Deubiquitylase OTUD3 regulates integrated stress response to suppress progression and sorafenib resistance of liver cancer

Deubiquitylase OTUD3 regulates integrated stress response to suppress progression and sorafenib resistance of liver cancer

  • Cell Rep. 2024 Jul 23;43(7):114487. doi: 10.1016/j.celrep.2024.114487.
Hongmiao Dai 1,  Bo Wu 2,  Yingwei Ge 2,  Yang Hao 2,  Lijie Zhou 3,  Ruolin Hong 4,  Jinhao Zhang 5,  Wenli Jiang 6,  Yuting Zhang 6,  Hongchang Li 7,  Lingqiang Zhang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 2 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China.
  • 3 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; School of Medicine, Tsinghua University, Beijing 100084, China.
  • 4 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China.
  • 5 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; Department of Cell Biology, School of Basic Medicine, Medical College, Qingdao University, Qingdao 266071, China.
  • 6 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; School of Life Sciences, Hebei University, Baoding, Hebei 071002, China.
  • 7 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China. Electronic address: lhc_lihongchang@126.com.
  • 8 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China. Electronic address: zhanglq@nic.bmi.ac.cn.
PMID: 38996071 DOI: 10.1016/j.celrep.2024.114487
Abstract

The integrated stress response (ISR) is activated in response to intrinsic and extrinsic stimuli, playing a role in tumor progression and drug resistance. The regulatory role and mechanism of ISR in liver Cancer, however, remain largely unexplored. Here, we demonstrate that OTU domain-containing protein 3 (OTUD3) is a deubiquitylase of eukaryotic initiation factor 2α (eIF2α), antagonizing ISR and suppressing liver Cancer. OTUD3 decreases interactions between eIF2α and the kinase EIF2ΑK3 by removing K27-linked polyubiquitylation on eIF2α. OTUD3 deficiency in mice leads to enhanced ISR and accelerated progression of N-nitrosodiethylamine-induced hepatocellular carcinoma. Additionally, decreased OTUD3 expression associated with elevated eIF2α phosphorylation correlates with the progression of human liver Cancer. Moreover, ISR activation due to decreased OTUD3 expression renders liver Cancer cells resistant to sorafenib, while the combined use of the ISR inhibitor ISRIB significantly improves their sensitivity to sorafenib. Collectively, these findings illuminate the regulatory mechanism of ISR in liver Cancer and provide a potential strategy to counteract sorafenib resistance.

Keywords

CP: Cancer; CP: Molecular biology.

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