Abstract
The role of ubiquitin in post-translational modifications is important for tumor progression, but how these mechanisms regulate bladder cancer (BLCA) is not completely known. The study demonstrated that FBXL6, a member of the F-box protein family, could drive oncogenesis in BLCA, as shown by integrative bioinformatic analysis and clinical sample validation. Experiments demonstrated that FBXL6 speeds up the in vitro growth and migration of BLCA cells and contributes to tumor development and metastasis in vivo. Mechanistically, transcriptomic and metabolic studies indicate that FBXL6 regulates the glycolytic pathway. Although FBXL6 knockdown has minimal impact on the mRNA levels of the key glycolytic enzyme ENO1, FBXL6 knockdown does alter ENO1 protein levels, suggesting post-translational regulation. Co-immunoprecipitation and GST pull-down assays validated the interaction between FBXL6 and ENO1, confirming that the LRR domain of FBXL6 and the C-terminal region of ENO1 are essential for their binding. Additionally, ubiquitination assays indicated that FBXL6 promotes K63-linked polyubiquitination of ENO1, which stabilizes it. Bringing back ENO1 expression partially offset the consequences of FBXL6 knockdown on proliferation and migration. In summary, our findings propose a new model where FBXL6 promotes BLCA progression by stabilizing ENO1 through K63 linkage, emphasizing its potential as a target for BLCA therapy.
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The excellent technical assistance of Ms. Mengxue Yu, Ms. Yayun Fang, Ms. Danni Shan, and Ms. Wan Xiang is gratefully acknowledged.
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This study was supported by the Research Fund of Zhongnan Hospital of Wuhan University (PTZX2025001 and PTPP2020006) and the National Natural Science Foundation of China (82504200).
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The animal study was performed in accordance with the relevant guidelines and was approved by the Experimental Animal Welfare Ethics Committee, Zhongnan Hospital of Wuhan University (approval no. ZN2024140). All clinical specimens were obtained with informed consent, and the study was approved by the Ethics Committee of Zhongnan Hospital (approval no. 2021125) and was performed in accordance with the relevant guidelines and regulations.
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Huang, R., Yu, J., Bai, R. et al. FBXL6 promotes bladder cancer progression by stabilizing ENO1 through K63-linked ubiquitination. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03130-x
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DOI: https://doi.org/10.1038/s41420-026-03130-x
