KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer

Disruption of KDM6A, a histone lysine demethylase, is one of the transcription factor ATF3, which in turn repressed FOXA1-target most common somatic alternations in bladder cancer. Insights into genes and activated cell-cycle progression genes. Importantly, ATF3 how KDM6A mutations affect the epigenetic landscape to promote depletion reversed the cell proliferation phenotype induced by carcinogenesis could help reveal potential new treatment KDM6A deficiency. These data establish that KDM6A loss engenapproaches. Here, we demonstrated that KDM6A loss triggers an ders an epigenetic state that drives tumor growth in an ATF3-epigenetic switch that disrupts urothelial differentiation and dependent manner, creating a potentially targetable molecular induces a neoplastic state characterized by increased cell prolifervulnerability. ation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differ-Significance: A gain-of-function epigenetic switch that disrupts entiation. KDM6A-deficient cells displayed simultaneous loss of differentiation is triggered by inactivating KDM6A mutations in FOXA1 target binding and genome-wide redistribution of the bZIP bladder cancer and can serve as a potential target for novel therapies.