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USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2

Oncogene (2024)Cite this article

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Abstract

Post-translational modifications of proteins play a pivotal role in both the initiation and progression of ovarian cancer. Despite the recognition of USP33 as a significant factor in various cancers, its specific function and underlying mechanisms in ovarian cancer remain elusive. Proteomics and ubiquitinomics approaches were coupled to screen novel substrate proteins directly regulated by USP33. Our findings unveil that USP33 was observed to eliminate K27- and K48-linked ubiquitin chains from CBX2 at the K277 position. Notably, acetylation of CBX2 at K199, catalyzed by lysine acetyltransferase GCN5, was found to enhance its interaction with USP33, subsequently promoting further deubiquitination and stabilization. Functionally, our experiments demonstrate that USP33 significantly enhances ovarian cancer proliferation and metastasis in a CBX2-dependent manner. Furthermore, analysis revealed a direct positive correlation between the expression levels of USP33 and CBX2 proteins in human specimens, with elevated levels being associated with reduced survival rates in ovarian cancer patients. These findings elucidate the mechanism by which USP33 augments ovarian cancer progression through the stabilization of CBX2, underscoring the USP33-CBX2 axis as a promising therapeutic target in ovarian cancer management.

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Fig. 1: USP33 as a binding protein of CBX2 in ovarian cancer.
Fig. 2: USP33 promotes CBX2 stability in ovarian cancer.
Fig. 3: USP33 deubiquitinates CBX2.
Fig. 4: USP33 promotes ovarian cancer progression in a CBX2-dependent manner.
Fig. 5: CBX2 acetylation at K199 facilitates the USP33-CBX2 interaction.
Fig. 6: Correlation between USP33 protein expression and CBX2 levels, and their prognostic implications in ovarian cancer patients.

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Data availability

All data required to evaluate the results are accessible within the article or the Supplementary Materials. The human sequence data generated in this study are not publicly available due to patient privacy requirements, but interested parties may request access to these data from the corresponding author.

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Funding

This work was supported by the Clinical Key Specialty Fund of Anhui Province (No. 2022sjlczdzk), USTC Research Funds of the Double First-Class Initiative (YD9110002049), Beijing Kanghua Traditional Chinese Medicine and the Western Medicine Development Foundation (No. KH-2021-LQJJ-008), National Natural Science Foundation of China (Grant Number: 81872430), Fund in China Postdoctoral Science Foundation (Nos. 2019T120281 and 2019M661304), and Heilongjiang Province Postdoctoral Science Foundation (No. LBH-Z18109).

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Author notes

  1. These authors contributed equally: Jiming Chen, Wulin Shan, Qiucheng Jia, Yao Chen.

Authors and Affiliations

  1. Department of Gynecology, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, China

    Jiming Chen & Qiucheng Jia

  2. Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China

    Wulin Shan, Wenjing Jiang, Yuan Tian, Xu Huang, Xiaoyu Li & Bairong Xia

  3. Department of Obstetrics and Gynecology, Anhui Provincial Cancer Hospital, Hefei, Anhui, China

    Wulin Shan, Yao Chen, Wenjing Jiang, Yuan Tian, Xu Huang, Xiaoyu Li, Zengying Wang & Bairong Xia

  4. Bengbu Medical University, Bengbu, Anhui, China

    Yao Chen, Zengying Wang & Bairong Xia

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Bairong Xia contributed to project design and provided financial support. Jiming Chen, Wulin Shan, Qiucheng Jia, and Yao Chen performed the majority of the experiments. Bairong Xia, Jiming Chen, Wulin Shan, and Yao Chen analyzed the data. Wulin Shan and Jiming Chen prepared this manuscript. Wenjing Jiang, Yuan Tian, Xu Huang, Xiaoyu Li, and Zengying Wang assisted with the collection and analysis of the clinical data. All authors have read and edited the paper.

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Correspondence to Bairong Xia.

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This study involving human participants and animals was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (2023-FLK-01). Written informed consent was obtained from all the patients. All methods were performed in accordance with the relevant guidelines and regulations.

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Chen, J., Shan, W., Jia, Q. et al. USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2. Oncogene (2024). https://doi.org/10.1038/s41388-024-03151-9

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