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DLGAP5 triggers proliferation and metastasis of bladder cancer by stabilizing E2F1 via USP11

Oncogene volume 43, pages 594–607 (2024)Cite this article

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Abstract

Bladder cancer (BLCA) is one of the most widespread malignancies worldwide, and displays significant tumor heterogeneity. Understanding the molecular mechanisms exploitable for treating aggressive BLCA represents a crucial objective. Despite the involvement of DLGAP5 in tumors, its precise molecular role in BLCA remains unclear. BLCA tissues exhibit a substantial increase in DLGAP5 expression compared with normal bladder tissues. This heightened DLGAP5 expression positively correlated with the tumor’s clinical stage and significantly affected prognosis negatively. Additionally, experiments conducted in vitro and in vivo revealed that alterations in DLGAP5 expression notably influence cell proliferation and migration. Mechanistically, the findings demonstrated that DLGAP5 was a direct binding partner of E2F1 and that DLGAP5 stabilized E2F1 by preventing the ubiquitination of E2F1 through USP11. Furthermore, as a pivotal transcription factor, E2F1 fosters the transcription of DLGAP5, establishing a positive feedback loop between DLGAP5 and E2F1 that accelerates BLCA development. In summary, this study identified DLGAP5 as an oncogene in BLCA. Our research unveils a novel oncogenic mechanism in BLCA and offers a potential target for both diagnosing and treating BLCA.

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Fig. 1: DLGAP5 expression was correlated with the degree of malignancy and prognosis of BLCA.
Fig. 2: DLGAP5 promotes BLCA proliferation and metastasis in vitro and in vivo.
Fig. 3: DLGAP5 sustains E2F1 stability by interacting with E2F1.
Fig. 4: DLGAP5 maintains E2F1 protein stability through USP11-mediated deubiquitination.
Fig. 5: E2F1 promotes the transcription of DLGAP5.
Fig. 6: DLGAP5 regulates BLCA proliferation and migration through E2F1.
Fig. 7: Diagram of the molecular mechanism.

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Data availability

The RNA-seq data produced in this research have been submitted to the GEO database with the accession code GSE241523. In Supplementary Dataset 1, we provide the results of mass spectrometry assays carried out in this study. Data from the GSE76211, GSE13507, GSE32548, GSE214212 and GSE95303 cohorts (described in Supplementary Table 8) are publicly available in the GEO database and were used in this study. UCSC Xena (https://xenabrowser.net/) was used to acquire the TCGA-BLCA cohort data. The remaining data can be accessed in the article or Supplementary information.

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Acknowledgements

Thanks to Dr. Yuruo Chen for exceptional assistance in editing the diagram. This work was supported by the National Natural Science Foundation of China (82172985), Research Fund of Zhongnan Hospital of Wuhan University (SWYBK01 and SWYBK02), and Fundamental Research Funds for the Central Universities (2042022dx0003). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. These authors contributed equally: Fenfang Zhou, Zhao Deng, Dexin Shen.

Authors and Affiliations

  1. Department of Urology, Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

    Fenfang Zhou, Zhao Deng, Dexin Shen, Mengxin Lu, Mingxing Li, Jingtian Yu, Yu Xiao & Xinghuan Wang

  2. Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Fenfang Zhou

  3. Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Dexin Shen

  4. Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China

    Yu Xiao, Gang Wang, Kaiyu Qian, Lingao Ju & Xinghuan Wang

  5. Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China

    Xinghuan Wang

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Contributions

FZ, YX, LJ and XW conceived and designed the study. FZ, ZD, DS, YX, GW and KQ performed the analysis procedures. FZ, ZD, DS, YX, LJ, and XW analyzed the results. YX, ZD, DS, M.Lu, M.Li, JY, and LJ contributed analysis tools. FZ, ZD, DS, YX, LJ, and XW contributed to the writing of the manuscript. All authors reviewed the manuscript.

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Correspondence to Lingao Ju or Xinghuan Wang.

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Zhou, F., Deng, Z., Shen, D. et al. DLGAP5 triggers proliferation and metastasis of bladder cancer by stabilizing E2F1 via USP11. Oncogene 43, 594–607 (2024). https://doi.org/10.1038/s41388-023-02932-y

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