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Molecular hydrogen suppresses activated Wnt/?-catenin signaling.

ABSTRACT: Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/?-catenin signaling by promoting phosphorylation and degradation ?f ?-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of ?-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the ?-catenin degradation complex, minimized the suppressive effect of H2 on ?-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of ?-catenin, as well as the ?-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/?-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating ?-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/?-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases.

SUBMITTER: Lin Y

PROVIDER: S-EPMC5001535 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Molecular hydrogen suppresses activated Wnt/β-catenin signaling.

Lin Yingni Y Ohkawara Bisei B Ito Mikako M Misawa Nobuaki N Miyamoto Kentaro K Takegami Yasuhiko Y Masuda Akio A Toyokuni Shinya S Ohno Kinji K

Scientific reports 20160825

Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylat ...[more]

PMID: 27558955

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Project description:Oxidants and canonical Wnt/?-catenin signaling have been shown to decrease cardiac Na(+) channel activity by suppressing NaV1.5 expression. Our aims are to determine if hydrogen peroxide (H2O2), one oxidant of reactive oxygen species (ROS), activates Wnt/?-catenin signaling and promotes ?-catenin nuclear activity, leading to suppression of NaV1.5 expression and if this suppression requires the interaction of ?-catenin with its nuclear partner, TCF4 (also called TCF7L2) to decrease SCN5a promoter activity. The results demonstrated that H2O2 increased ?-catenin, but not TCF4 nuclear localization determined by immunofluorescence without affecting total ?-catenin protein level. Furthermore, H2O2 exerted a dose- and time-dependent suppressive effect on NaV1.5 expression. RT-PCR and/or Western blot analyses revealed that overexpressing active form of ?-catenin or stabilizing ?-catenin by GSK-3? inhibitors, LiCl and Bio, suppressed NaV1.5 expression in HL-1 cells. In contrast, destabilization of ?-catenin by a constitutively active GSK-3? mutant (S9A) upregulated NaV1.5 expression. Whole-cell recording showed that LiCl significantly inhibited Na(+) channel activity in these cells. Using immunoprecipitation (IP), we showed that ?-catenin interacted with TCF4 indicating that ?-catenin as a co-transfactor, regulates NaV1.5 expression through TCF4. Analyses of the SCN5a promoter sequences among different species by using VISTA tools indicated that SCN5a promoter harbors TCF4 binding sites. Chromatin IP assays demonstrated that both ?-catenin and TCF4 were recruited in the SCN5a promoter, and regulated its activity. Luciferase promoter assays exhibited that ?-catenin inhibited the SCN5a promoter activity at a dose-dependent manner and this inhibition required TCF4. Small interfering (Si) RNA targeting ?-catenin significantly increased SCN5a promoter activity, leading to enhanced NaV1.5 expression. As expected, ?-catenin SiRNA prevents H2O2 suppressive effects on both SCN5a promoter activity and NaV1.5 expression. Our findings indicate that H2O2 inhibits NaV1.5 expression by activating the Wnt/?-catenin signaling and ?-catenin interacts with TCF4 to transcriptionally suppress cardiac NaV1.5 expression.

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Molecular hydrogen suppresses activated Wnt/?-catenin signaling.

Publications

Molecular hydrogen suppresses activated Wnt/β-catenin signaling.

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