FBXL6 promotes bladder cancer progression by stabilizing ENO1 through K63-linked ubiquitination

Here, we identified FBXL6, belonging to the F-box protein family, as a potential oncogenic driver in BLCA through integrative bioinformatic analysis of multiple public datasets and validation in clinical specimens. Functional analyses demonstrated that FBXL6 accelerates both the in vitro proliferation and migration of BLCA cells and the in vivo progression of tumors and metastatic spread.

Mechanistically, transcriptomic profiling and metabolic analyses suggested that FBXL6 regulates glycolysis, with particular involvement of the glycolytic enzyme ENO1. While ENO1 mRNA remained largely unchanged upon FBXL6 knockdown, Western blot analysis revealed corresponding changes in ENO1 protein levels, indicating post-transcriptional regulation. Co-immunoprecipitation assays confirmed a physical interaction between FBXL6 and ENO1, and domain-mapping analysis revealed that the leucine-rich repeat (LRR) region of FBXL6 mediates ENO1 binding.