ZW4864 ‐mediated inhibition of the β‐catenin/ BCL9 / BCL9L complex reveals therapeutic potential in bladder cancer

Bladder cancer is the most prevalent malignancy of the urinary tract; nevertheless, its progression and treatment continue to pose substantial challenges. While the molecular mechanisms underlying bladder cancer progression remain unknown, the Wnt/β‐catenin signaling pathway has established roles in cancer progression. In this study, we investigated the contribution of BCL9(L) (coactivators of β‐catenin) to bladder cancer progression and evaluated the therapeutic potential of disrupting the β‐catenin/BCL9(L) complex. We demonstrate that BCL9L exerts oncogenic effects on the proliferation and invasion of bladder cancer cells and the knockdown of BCL9 also reduced the proliferation, migration, and invasion of bladder cancer cells, suggesting similar oncogenic roles. Pharmacological inhibition of the β‐catenin/BCL9(L) complex using ZW4864 suppresses a subset of Wnt/β‐catenin targets in bladder cancer cells, indicating the inhibition of canonical Wnt signaling. We show ZW4864 has an inhibitory effect on the proliferation, migration, and invasion of bladder cancer cells and impedes the growth and formation of multicellular bladder cancer organoids. These findings demonstrate the crucial role of BCL9 and BCL9L in bladder cancer progression and highlight the β‐catenin/BCL9(L) axis as a promising therapeutic target.