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

SUBMITTER: Kaneko S

PROVIDER: S-EPMC6007159 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Kaneko Satoshi S Li Xue X

Science advances 20180613 6

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 (KDM6A) is a sexually dimorphic gene. Wild-type but not catalytically dead KDM6A confers sustained tumor suppressor activity in vitro. K ...[more]

PMID: 29928692

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Project description:Recently, numerous evidence has revealed that excessive reactive oxygen species (ROS) production and mitochondrial disruption during acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS) will aggravate the inflammatory process. To identify whether antioxidation can be one of the treatment strategies during this progress, we chose mitoQ, a mitochondria-targeted antioxidant that was proved to be effective in reducing ROS generated in mitochondria, as a ROS scavenger to investigate the role of antioxidation in ALI. We demonstrated that overoxidation occurred during the process of ALI, which could be reduced by mitoQ. In the meantime, apoptosis of endothelial cells of ALI mice, accompanied by hyperpermeability of pulmonary vascular and impaired pulmonary function, was partially reversed following an intraperitoneal injection of mitoQ. Moreover, in in vitro study, lipopolysaccharides (LPS) induced excessive ROS production, mitochondrial dysfunction and apoptosis in human pulmonary microvascular endothelial cells (HPMECs), which were rectified by mitoQ. To explore underlying mechanisms, we proceeded RNA-sequencing and found significantly upregulated expression of musculoaponeurotic fibrosarcoma F (MafF) in mitoQ treated group. Additionally, mitoQ inhibited the degradation and increased nuclear translocation of NF-E2-related factor 2 (Nrf2) and upregulated its downstream antioxidant response elements (AREs), such as heme oxygenase (HO)-1 and NAD(P)H:quinone oxidoreductase (NQO)-1. This effect was abolished by transfecting HPMECs with Nrf2 or Maff siRNA. In Nrf2 deficient mice, the protective effects of mitoQ on LPS model of ALI were largely vanished. Taken together, these results provide insights into how antioxidation exerts beneficial effects on ALI via maintaining mitochondrial hemostasis, inhibiting endothelial cells apoptosis, attenuating the endothelial disruption and regulating lung inflammation via Nrf2-MafF/ARE pathway.

Dataset Information

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

Publications

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

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