FGF-2 Regulates Cell Proliferation, Migration, and Angiogenesis through an NDY1/KDM2B-miR-101-EZH2 Pathway

• Published in: Molecular cell Vol. 43; no. 2; pp. 285 - 298
• Main Authors: Kottakis, Filippos, Polytarchou, Christos, Foltopoulou, Parthena, Sanidas, Ioannis, Kampranis, Sotirios C., Tsichlis, Philip N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.07.2011
• Subjects: angiogenesis; Animals; carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer of Zeste Homolog 2 Protein; F-Box Proteins - genetics; F-Box Proteins - metabolism; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Histone Demethylases - metabolism; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; histones; Humans; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; methyltransferases; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Neovascularization, Physiologic; Oxidoreductases, N-Demethylating - genetics; Oxidoreductases, N-Demethylating - metabolism; phosphorylation; Polycomb Repressive Complex 2; Transcription Factors - genetics; Transcription Factors - metabolism; urinary bladder neoplasms
• DOI: 10.1016/j.molcel.2011.06.020
• ISSN: 1097-2765

The histone H3K27 methyltransferase EZH2 plays an important role in oncogenesis, by mechanisms that are incompletely understood. Here, we show that the JmjC domain histone H3 demethylase NDY1 synergizes with EZH2 to silence the EZH2 inhibitor miR-101. NDY1 and EZH2 repress miR-101 by binding its promoter in concert, via a process triggered by upregulation of NDY1. Whereas EZH2 binding depends on NDY1, the latter binds independently of EZH2. However, both are required to repress transcription. NDY1 and EZH2 acting in concert upregulate EZH2 and stabilize the repression of miR-101 and its outcome. NDY1 is induced by FGF-2 via CREB phosphorylation and activation, downstream of DYRK1A, and mediates the FGF-2 and EZH2 effects on cell proliferation, migration, and angiogenesis. The FGF-2-NDY1/EZH2-miR-101-EZH2 axis described here was found to be active in bladder cancer. These data delineate an oncogenic pathway that functionally links FGF-2 with EZH2 via NDY1 and miR-101. [Display omitted] ► Pathway linking FGF-2 with epigenetic regulation of gene expression ► NDY1 upregulation triggers the binding of EZH2 and NDY1 to the miR-101 locus ► Activation of this pathway is essential for the biology elicited by FGF-2 ► The pathway is active in normal cells, tumor cell lines, and primary tumors