# YKT6 Promotes Bladder Cancer Progression by Stabilizing β‐catenin Through USP7‐Mediated Deubiquitination

## TL;DR

YKT6, a protein, promotes bladder cancer by stabilizing β-catenin through USP7, offering a new target for treatment.

## Contribution

YKT6 is identified as a novel regulator of Wnt signaling via USP7-mediated β-catenin stabilization in bladder cancer.

## Key findings

- YKT6 is upregulated in bladder cancer and linked to poor patient outcomes.
- YKT6 stabilizes β-catenin through USP7, activating Wnt signaling and promoting cancer progression.
- Inhibiting Wnt signaling reverses YKT6-driven malignancy, confirming the axis as a therapeutic target.

## Abstract

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. It is demonstrated that YKT6 is significantly upregulated in BLCA tissues and cell lines, correlating with advanced tumor grade, aggressive histology, and poor patient prognosis from public datasets and tissue microarray. 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/β‐catenin signaling pathway through a novel mechanism involving USP7‐mediated deubiquitination of β‐catenin. By recruiting USP7, YKT6 inhibits β‐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 demonstrate that Wnt signaling inhibition reverses YKT6‐driven malignant effects, while pathway activation restores tumor progression in YKT6‐silenced cells. USP7 knockdown abrogates YKT6‐mediated β‐catenin stabilization, confirming their functional interdependence. Clinically, the YKT6/USP7/β‐catenin axis strongly correlates with poor prognosis, providing a proof‐of‐concept for the druggability of this axis. The findings unveil YKT6 as a novel regulator of Wnt signaling through USP7‐dependent deubiquitination, offering insights for precision BLCA therapy.

The SNARE protein YKT6 is upregulated in bladder cancer (BLCA), correlating with poor prognosis. YKT6 promotes tumor proliferation and metastasis by activating Wnt/β‐catenin signaling. It recruits Ubiquitin‐Specific Peptidase 7 (USP7) to deubiquitinate and stabilize β‐catenin, enhancing its nuclear accumulation and driving oncogenic gene expression. The YKT6/USP7/β‐catenin axis represents a potential therapeutic target in BLCA.