X chromosome protects against bladder cancer in females via a <i>KDM6A</i>-dependent epigenetic mechanism.

Abstract

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 (<i>KDM6A</i>) is a sexually dimorphic gene. Wild-type but not catalytically dead <i>KDM6A</i> confers sustained tumor suppressor activity in vitro. Knockout of mouse <i>Kdm6a</i> reduces expression of <i>Cdkn1a</i> and <i>Perp</i>, canonical gene targets of the tumor suppressor <i>p53</i>. Consistently, loss of <i>Kdm6a</i> increases BCa risk in female mice, and mutations or reduced expression of human <i>KDM6A</i> predicts poor prognosis of female BCa patients. Collectively, the study reveals that the X chromosome protects against BCa among females via a <i>KDM6A</i>-dependent epigenetic mechanism and further suggests that <i>KDM6A</i> is a prototypical sex-biasing tumor suppressor with both demethylase-dependent and demethylase-independent activities.