X chromosome protects against bladder cancer in females via a -dependent epigenetic mechanism.

Men are much more likely than women to develop bladder cancer (BCa), but the underlying cause of this gender disparity remains poorly defined. Using sex-reversed mice, we show that the sex chromosome complement is an independent cause and, moreover, amplifies the biasing effects of sex hormones. We also show that the X-linked lysine demethylase 6A () is a sexually dimorphic gene. Wild-type but not catalytically dead confers sustained tumor suppressor activity in vitro. Knockout of mouse reduces expression of and , canonical gene targets of the tumor suppressor . Consistently, loss of increases BCa risk in female mice, and mutations or reduced expression of human predicts poor prognosis of female BCa patients. Collectively, the study reveals that the X chromosome protects against BCa among females via a -dependent epigenetic mechanism and further suggests that is a prototypical sex-biasing tumor suppressor with both demethylase-dependent and demethylase-independent activities.