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

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 2? (eIF2?), antagonizing ISR and suppressing liver cancer. OTUD3 decreases interactions between eIF2? and the kinase EIF2?K3 by removing K27-linked polyubiquitylation on eIF2?. OTUD3 deficiency in mice leads to enhanced ISR and accelerated progression of N-nitrosodiethylamine-induced hepatocellular carcinoma. Additionally, decreased OTUD3 expression associated with elevated eIF2? 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.
Mesh Terms:
Animals, Carcinoma, Hepatocellular, Cell Line, Tumor, Disease Progression, Drug Resistance, Neoplasm, Eukaryotic Initiation Factor-2, Humans, Liver Neoplasms, Mice, Mice, Inbred C57BL, Phosphorylation, Sorafenib, Stress, Physiological, Ubiquitin-Specific Proteases, Ubiquitination
Cell Rep
Date: Jul. 23, 2024
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