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BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking SIRT2 activity

Oncogene volume 44, pages 665–678 (2025)Cite this article

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A Correction to this article was published on 22 January 2025

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Abstract

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, the role of brain-expressed X-linked 4 (BEX4) in cancer progression has received increasing attention. This study aimed to investigate the function of BEX4 in ccRCC and to reveal the underlying mechanisms. We first confirmed that BEX4 was significantly downregulated in ccRCC by bioinformatics analysis and that patients with low BEX4 expression tended to have prolonged overall survival time. Subsequently, we confirmed that BEX4 inhibited ccRCC cell proliferation in vitro and tumorigenesis in vivo through a series of cell function assays and the establishment of a nude mouse xenograft model, respectively. Mechanistically, we found that BEX4 positively regulates the expression of Src homology 2 domain-containing 4A (SH2D4A), an inhibitor of the NOTCH pathway, which further promoted the tumor-suppressive effects of BEX4. In addition, our study confirmed that the promoting effect of BEX4 on SH2D4A was achieved by inhibiting the deacetylase sirtuin 2 (SIRT2) activity. On this basis, we found that there was a competition between acetylation and ubiquitination modifications at the K69 site of SH2DA4 and that BEX4-induced upregulation of acetylation at the k69 site stabilizes SH2D4A protein expression by inhibiting ubiquitination at the same site. In addition, dual-luciferase assays showed that the transcriptional activity of BEX4 was positively regulated by activation transcription factor 3 (ATF3). Our study suggests that BEX4 plays a role in inhibiting tumor progression in ccRCC and maybe a new diagnostic and therapeutic target for ccRCC patients.

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Fig. 1: BEX4 is low expressed in clear cell renal cell carcinoma (ccRCC) and is associated with a favorable prognosis.
Fig. 2: BEX4 inhibits ccRCC cell proliferation and regulates cell cycle progression in vitro.
Fig. 3: BEX4 inhibits the proliferation of ccRCC cells in vivo.
Fig. 4: BEX4 inhibits the malignant phenotype of ccRCC by promoting the expression of SH2D4A.
Fig. 5: BEX4 inhibits the NOTCH signaling pathway by promoting SH2D4A expression.
Fig. 6: BEX4 promotes the acetylation of SH2D4A and inhibits ubiquitination by inhibiting the activity of SIRT2.
Fig. 7: SH2D4A acetylation at K69 stabilizes the protein by blocking its ubiquitination.
Fig. 8: BEX4 is transcriptionally regulated by ATF3 in ccRCC.

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Data will be made available on request

Change history

  • 20 January 2025

    The original online version of this article was revised: In this article the affiliation details for Author Shiyong Xin were incorrectly given as '1Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. 4Department of Urology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. 9These authors contributed equally: Ziyao Li, Shiyong Xin, Liqun Huang.' but should have been '4Department of Urology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. 9These authors contributed equally: Ziyao Li, Shiyong Xin, Liqun Huang.

  • 22 January 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41388-025-03278-3

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Acknowledgements

This research was funded by the China Scholarship Council (No. 202007045011) and the Excellent Young Medical Talents Training Project of Pudong New Area Health Committee (No. PWRq2020-43).

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Author notes

  1. These authors contributed equally: Ziyao Li, Shiyong Xin, Liqun Huang.

Authors and Affiliations

  1. Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

    Ziyao Li, Liqun Huang, Weihua Chen, Bowen Ye, Guosheng Yang & Lin Ye

  2. School of Electrical Engineering of Zhengzhou University, Zhengzhou, China

    Ziyao Li

  3. Center for Frontier Medical Engineering of Chiba University, Chiba, Japan

    Ziyao Li

  4. Department of Urology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China

    Shiyong Xin

  5. Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, China

    Ye Tian

  6. Department of Urology, Putuo People’s Hospital, School of Medicine, Tongji University, Shanghai, China

    Xiang Liu

  7. Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

    Rong Bai

  8. Department of Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, China

    Wenwen Wang

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Contributions

Lin Ye, Wenwen Wang, and Guosheng Yang: Conceived and designed the experiments. ZiYao Li, Shiyong Xin and Liqun Huang: Performed the experiments, Analyzed and interpreted the data. Ye Tian, Weihua Chen and Xiang Liu: Contributed reagents, materials, analysis tools or data. Bowen Ye, and Rong Bai: Analyzed and interpreted the data. ZiYao Li: Wrote the original draft. Lin Ye: Revised manuscript. All authors have critically revised manuscript and approved its final version.

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Correspondence to Guosheng Yang, Wenwen Wang or Lin Ye.

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Li, Z., Xin, S., Huang, L. et al. BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking SIRT2 activity. Oncogene 44, 665–678 (2025). https://doi.org/10.1038/s41388-024-03235-6

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