KDM6A loss triggers an epigenetic switch that disrupts urothelial identity and drives cell proliferation in bladder cancer

Chromatin modifiers regulate gene expression in many biologic contexts such as development, differentiation, and homeostasis. Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alterations in both non-muscle invasive and muscle invasive bladder cancer. We demonstrate that KDM6A loss triggers an epigenetic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In luminal subtype bladder cancer cells with intact KDM6A, FOXA1 binds KDM6A at enhancers to activate genes directing urothelial differentiation. In addition to loss of FOXA1 target binding, KDM6A deletion alters chromatin accessibility to permit genome-wide redistribution of the transcription factor ATF3. In KDM6A-deficient cells, ATF3 represses FOXA1-target genes and activates genes associated with cell cycle progression; and ATF3 depletion reverses the cell proliferation phenotype. Taken together, these data suggest that KDM6A loss creates an epigenetic vulnerability that can be leveraged with novel therapeutic strategies.