PRJNA822231
KDM6A loss triggers an epigenetic switch that disrupts urothelial identity and drives cell proliferation in bladder cancer
Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. How mutations of this chromatin modifier impact the epigenetic landscape to promote carcinogenesis is poorly understood. Here, we demonstrate that KDM6A loss triggers an epigenomic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1binds KDM6A at enhancers to activate genes instructing urothelial differentiation. In KDM6Adeficient cells, we observed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn represses FOXA1-target genes and activates cell cycle progression genes. Importantly, ATF3 depletion reverses the cell proliferation phenotype. These data establish that KDM6A loss creates an epigenetic state that drives tumor growth in an ATF3-dependent manner, forging a molecular vulnerability that can betargeted by novel therapeutic strategies.