Abstract
Bladder cancer (BLCA) is a growing health burden with rising incidence and limited therapeutic options. To define the role of the Tripartite Motif (TRIM) family in BLCA, we integrated multi-cohort transcriptomic analyses with functional and mechanistic validation. TRIM28 was identified as the most consistently upregulated TRIM member in BLCA and correlated with poor prognosis. TRIM28 depletion suppressed, whereas its overexpression enhanced, BLCA cell proliferation. Mechanistically, TRIM28 directly bound to PPARG and acted as a SUMO E3 ligase to catalyze SUMOylation of PPARG at Lys94 within a noncanonical YKYD motif. This modification impaired PPARG recognition by the E3 ubiquitin ligase STUB1, reduced ubiquitin-proteasome degradation, and stabilized PPARG protein. Stabilized PPARG transcriptionally activated cholesterol biosynthetic genes, including DHCR7 and DHCR24, reprogramming cholesterol metabolism to promote BLCA progression. In summary, we identify a TRIM28-PPARG SUMO-ubiquitin crosstalk axis that drives metabolic remodeling and tumor growth in BLCA, highlighting TRIM28-mediated PPARG SUMOylation as a potential therapeutic target for metabolic intervention.
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Data availability
Data from the GSE13507, GSE32894 and TCGA cohorts are publicly available and are used in this study. RNA-seq data is uploaded to GEO database, and the GEO accession number is GSE318442. Proteins that interact with Flag-TRIM28 is provided in the data repository as supplementary information. Code is available from the corresponding author upon reasonable request.
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Acknowledgements
We sincerely appreciate assistance from Medical Research Center of Anhui Provincial Hospital in providing convenient experimental conditions.
Funding
This study is supported by grants from the Major Clinical Department Construction Project of Anhui Province (340000222428003000020-2023-4); the Major Project of the Department of Education of Anhui Province (NO. 2022AH040182); the Health Research Project of Anhui Province (AHWJ2023A30269); the USTC Research Funds of the Double First-Class Initiative (YD9110002098; YD9110002129); the Anhui Postdoctoral Scientific Research Program Foundation (No. 2025B1051); the China Postdoctoral Science Foundation funded project (No. 2025M772207). The funders play no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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XFF, ZXL, DXS and JX conceived and designed the study, XFF, ZXL, QQG, PZH, ZYL, DML, LW, PX performed the experiments and analyzed the results, TH, DXS, and JX contributed to the writing of the manuscript. All authors reviewed the manuscript. All authors agree to submit this version of the manuscript.
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The Ethics committee of experimental animals of The First Affiliated Hospital of University of Science and Technology of China granted ethical approval for this study (approval number: 2025-N(A)-176).
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Fan, X., Li, Z., Gao, Q. et al. TRIM28 orchestrates SUMO-ubiquitin crosstalk to stabilize PPARG and drive bladder cancer progression. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08745-7
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DOI: https://doi.org/10.1038/s41419-026-08745-7
