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Crosstalk between SUMOylation and ubiquitination controls the stability of transcription factor zinc finger protein 24: a novel antitumor mechanism in bladder cancer

Oncogene (2025)Cite this article

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Abstract

Zinc finger protein 24 (ZNF24) is a conserved multifunctional transcription factor associated with tumorigenesis, but its function in bladder carcinogenesis remains unclear. Herein, the expression of ZNF24 was decreased in bladder cancer (BC) cells and tissues, and patients with higher expression of ZNF24 had a better prognosis. Doxycycline-induced overexpression and knockdown of ZNF24 identified its anti-proliferative and anti-metastasis role in BC in vitro and in vivo. The potential genes for the anti-cancer role of ZNF24, involving transcriptional regulation of several factors, such as dual-specificity phosphatase 1 and squalene epoxidase. E2 conjugating enzyme UBC9 and small ubiquitin-like modifier (SUMO) 1 were found to interact with ZNF24, suggesting that ZNF24 may be SUMOylated. Consistent with the expression, ZNF24 SUMOylation levels were decreased in BC cells and tissues. Pan-SUMOylation inhibition promoted protein degradation of ZNF24. UBC9 SUMOylated ZNF24 at Lys-27 (K27) site with SUMO1 modification and the K27 mutation of ZNF24 greatly damaged the protein stability of ZNF24. Cullin 3 (CUL3), a E3 ubiquitin ligase, was responsible for the degradation of ZNF24. ZNF24 SUMOylation prevented CUL3-mediated protein degradation of ZNF24. Overall, the crosstalk between the SUMOylation and ubiquitination of ZNF24 may be a novel regulatory mechanism to block tumorigenesis and development of BC.

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Fig. 1: ZNF24 is downregulated in BC tissues and cells and ZNF24 is positively correlated with prognosis of BC patients.
Fig. 2: ZNF24 suppresses cell growth in vitro.
Fig. 3: ZNF24 suppresses cell growth in vivo.
Fig. 4: ZNF24 inhibits BC cell metastasis in vitro and in vivo.
Fig. 5: The potential target genes of ZNF24 are identified by ChIP-seq combined with mRNA-seq.
Fig. 6: Analysis of potential downstream target genes of ZNF24.
Fig. 7: ZNF24 is SUMOylated with SUMO-1/2 and ZNF24 SUMOylation is decreased in BC cells and tissues, pan-SUMOylation inhibition of ZNF24 promotes protein degradation of ZNF24 by inhibiting the ubiquitin-proteasome pathway.
Fig. 8: UBC9 increases ZNF24 SUMOylation and ZNF24 is SUMOylated at K27 in a UBC9-dependent manner.
Fig. 9: SUMOylation inhibits protein degradation of ZNF24 mediated by CUL3.

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Data availability

All data are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 82373077 and 82373947) and the Science and Technology Research Project of Henan Province (Grant No. 242102310115 and 242102310397).

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  1. These authors contributed equally: Xiaosong Wei, Beibei Wang.

Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Xiaosong Wei, Yang Yang, Zhiwei Fang, Chengzhi Yi, Liuhui Zhang, Xin Fan, Dongdong Tang, Xiaoming Yang & Dongkui Song

  2. Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Beibei Wang

  3. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China

    Lirong Zhang

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  1. Xiaosong Wei
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Contributions

Conceptualization, Writing—original draft, and Writing—review and editing: XW, BW, XY, and DS; Data curation, Methodology, and Validation: XW, BW, YY, ZF, and CY; Software and Formal analysis: XW, BW, LZ, XF, DT, and LZ; Supervision, Project administration, and Funding acquisition: XW, XY, and DS.

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Correspondence to Xiaosong Wei, Xiaoming Yang or Dongkui Song.

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The informed consents were obtained from all participants. All human experiments were approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University. All animal experiments were conducted following the guidelines of the Institutional Committee for Animal Care and Use and the ethics committee of the First Affiliated Hospital of Zhengzhou University.

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Wei, X., Wang, B., Yang, Y. et al. Crosstalk between SUMOylation and ubiquitination controls the stability of transcription factor zinc finger protein 24: a novel antitumor mechanism in bladder cancer. Oncogene (2025). https://doi.org/10.1038/s41388-025-03450-9

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