The deubiquitinase OTUD1 orchestrates cisplatin chemosensitivity of non-small cell lung cancer through destabilizing RAD23B/XPC

Lung cancer, especially the subgroup non-small cell lung cancer (NSCLC), continues to be one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide. Cisplatin has long been a cornerstone of chemotherapy and has improved the prognosis for NSCLC patients. However, its overall efficacy remains unsatisfactory, and patients ultimately develop drug resistance. Uncovering the underlying mechanism and identifying potential target to enhance cisplatin chemosensitivity is urgent. In this study, we uncovered that OTU deubiquitinase 1 (OTUD1) plays an important role in orchestrating cisplatin chemosensitivity of NSCLC. We found that promoter methylation resulted in downregulation of OTUD1 and the downregulated OTUD1 significantly associates with cisplatin resistance and poor prognosis in NSCLC. Overexpression of OTUD1 enhances cisplatin sensitivity in vitro and in vivo. Mechanistically, OTUD1 promoted the degradation of RAD23B-XPC complex, which is the critical factor for nucleotide excision repair to remove cisplatin-induced DNA adducts, leading to cisplatin-induced cell death. OTUD1 cleaves the K63-linked ubiquitin chain of RAD23B and XPC, and enhances PRKN mediated K48-linked ubiquitination of RAD23B-XPC and the subsequent proteasomal degradation. The findings of this study highlighted that OTUD1 could be a potential therapeutic target for NSCLC.