YKT6 promotes bladder cancer progression by stabilizing ß-Catenin via USP7-mediated deubiquitination

Bladder cancer (BLCA) remains a highly lethal genitourinary malignancy with complex tumor biology and limited therapeutic strategies. This study investigates the oncogenic role of YKT6, a SNARE protein, in BLCA progression and molecular mechanisms. We demonstrate that YKT6 is significantly upregulated in BLCA tissues and cell lines, correlating with advanced tumor grade, aggressive histology, and poor patient prognosis. Comprehensive transcriptomic and functional analyses reveal that YKT6 promotes BLCA cell proliferation, migration, and metastasis both in vitro and in vivo. Mechanistically, YKT6 activates the Wnt/ß-catenin signaling pathway through a novel mechanism involving USP7-mediated deubiquitination of ß-catenin. By recruiting USP7, YKT6 inhibits ß-catenin's proteasomal degradation, thereby stabilizing the protein and driving nuclear accumulation. This stabilization leads to increased expression of oncogenic target genes and induces epithelial-mesenchymal transition (EMT). Pharmacological interventions demonstrated that Wnt signaling inhibition reverses YKT6-driven malignant effects, while pathway activation restores tumor progression in YKT6-silenced cells. USP7 knockdown abrogates YKT6-mediated ß-catenin stabilization, confirming their functional interdependence. Clinically, the YKT6/USP7/ß-catenin axis strongly correlates with poor prognosis, highlighting its potential as a diagnostic and therapeutic target. Our findings unveil YKT6 as a novel regulator of Wnt signaling through USP7-dependent deubiquitination, offering promising insights for precision BLCA therapy. Overall design: To uncover the underlying mechanism by which YKT6 promotes BLCA tumor growth and metastasis, RNA-seq analysis was performed on 5637 cells transfected with siNC or siYKT6.