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

Oncogene volume 44, pages 4855–4867 (2025) Cite this article

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Abstract

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.

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Fig. 1: OTUD1 is downregulated in CDDP resistant cells.
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Fig. 2: The downregulation of OTUD1 results from promoter methylation and associates with poor prognosis in human NSCLC.
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Fig. 3: OTUD1 enhances CDDP sensitivity in NSCLC cells.
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Fig. 4: OTUD1 interacts with RAD23B and XPC.
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Fig. 5: OTUD1 negatively regulates RAD23 and XPC and enhances CDDP-induced DNA damage.
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Fig. 6: OTUD1 cooperates with PRKN to promote degradation of RAD23B and XPC through the UPS.
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Data availability

The bulk RNA sequencing dataset in this study has been deposited to the NCBI Gene Expression Omnibus database and the accession number is GEO: GSE295626 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295626). Any data used in this study that are not included in the paper or supplementary files can be made available upon request from the corresponding author.

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Acknowledgements

The authors sincerely thank Prof. Tiebang Kang (Sun Yat-sen University, Guangzhou, China) for sharing V5-TurboID plasmids. This work was supported by the National Natural Science Foundation of China (Grant No. 81974364, 82373085, 82170758, 82472654, and 82473240), the Natural Science Foundation and Science and Technology Project of Guangdong Province (2022A1515010071, 2021A1515012321, 2021B1515020075), the Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A, TJYXZDXK-3-004B).

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  1. These authors contributed equally: Zhiqiang Wu, Meixi Wang, Xiaohan Dong, Yanchen Sun.

Authors and Affiliations

  1. Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Zhiqiang Wu, Xiaohan Dong, Yanchen Sun, Lu Zhang, Mi Tang & Zhiyong Yuan

  2. Department of Public Laboratory, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Meixi Wang & Zeyun Mi

  3. Department of Thoracic Medical Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China

    Xiangli Jiang

  4. Department of General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Yu Guo, Jing Wang & Weiwei Wang

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  1. Zhiqiang Wu
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Contributions

ZW, MW, XD and YS were responsible for designing, performing the experiments, and analyzing data. LZ, MT, XJ, YG, JW and WW assist the experiments, analyzing data, collecting patient specimens and information and evaluating of clinical data. ZW, MW and ZM drafted the manuscript. XJ and ZY commented and revised the manuscript. ZW and ZM designed the experiments, and conceived and supervised the study.

Corresponding authors

Correspondence to Zhiqiang Wu or Zeyun Mi.

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The authors declare no competing interests.

Ethics statement

This study was approved by the Institutional Review Board (IRB) of Tianjin Medical University Cancer Institute & Hospital and conducted in strict accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient before enrollment. All animal experiments were approved by the Institutional Animal Care and Use Committee of Tianjin Medical University Cancer Institute and Hospital and conducted in accordance with the guidelines of the Institutional Animal Care and Use Committees of the NIH Guide. All methods were performed in accordance with the relevant guidelines and regulations.

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Wu, Z., Wang, M., Dong, X. et al. The deubiquitinase OTUD1 orchestrates cisplatin chemosensitivity of non-small cell lung cancer through destabilizing RAD23B/XPC. Oncogene 44, 4855–4867 (2025). https://doi.org/10.1038/s41388-025-03647-y

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