Abstract
Abstract The histone H3K27 methyltransferase EZH2 plays an important role in oncogenesis, by mechanisms that are incompletely understood. Here we show that NDY1/KDM2B, a JmjC domain-containing histone H3K36me2, H3K36me1 and H3K4me3 demethylase synergizes with EZH2 to silence the EZH2 inhibitor miR-101. NDY1/KDM2B and EZH2 repress miR-101 by binding its promoter in concert via a process that is activated by upregulation of NDY1/KDM2B. EZH2 does not bind the miR-101 promoter when overexpressed in the absence of NDY1/KDM2B, while NDY1/KDM2B binds the miR-101 promoter when overexpressed in the absence of EZH2, but fails to repress transcription. The concerted action of NDY1/KDM2B and EZH2, triggered by the upregulation of NDY1/KDM2B, promotes the initial upregulation of EZH2 and initiates a feedforward loop that results to the gradual upregulation of EZH2 and other miR-101 targets. NDY1/KDM2B expression was induced by FGF-2 and to a lesser degree by VEGF, via CREB phosphorylation and activation, downstream of the DYRK1A kinase. The FGF-2-NDY1-miR-101-EZH2 axis was documented in primary fibroblasts in culture, and in a set of human tumor cell lines, and it was shown to be responsible for the FGF-2 and EZH2 effects on cell proliferation, migration and angiogenesis. The axis appeared to also be active in a set of transitional cell bladder carcinomas, in which NDY1/KDM2B and FGF-2 were overexpressed in concert and their upregulation correlated with the repression of miR-101 and the upregulation of EZH2. These data delineate a novel pathway that links FGF-2 signaling with the functional and transcriptional regulation of EZH2 via NDY1/KDM2B and miR-101, and contributes to oncogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 108. doi:10.1158/1538-7445.AM2011-108
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