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FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway

Filippos Kottakis1, Christos Polytarchou, Parthena Foltopoulou

  • 1Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.

Molecular Cell
|July 23, 2011
PubMed

Insights

The histone demethylase NDY1 and EZH2 collaborate to suppress miR-101, a key inhibitor of EZH2. This interaction drives oncogenesis and is active in bladder cancer, revealing a novel oncogenic pathway.

Area of Science:

  • Epigenetics
  • Molecular Oncology
  • Cancer Biology

Background:

  • Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase crucial in oncogenesis.
  • The precise mechanisms underlying EZH2's role in cancer remain incompletely understood.
  • MicroRNAs (miRNAs) are key regulators of gene expression implicated in cancer development.

Purpose of the Study:

  • To elucidate the functional relationship between NDY1, EZH2, and miR-101 in oncogenesis.
  • To identify the molecular pathway linking FGF-2, NDY1, EZH2, and miR-101.
  • To investigate the activity of this pathway in bladder cancer.

Main Methods:

  • Investigated the synergistic action of NDY1 and EZH2 on miR-101 promoter activity.
  • Analyzed the binding of NDY1 and EZH2 to the miR-101 promoter.
  • Examined the induction of NDY1 by FGF-2 and its downstream effects.
  • Assessed the expression and activity of the FGF-2-NDY1/EZH2-miR-101 axis in bladder cancer samples.

Main Results:

  • NDY1 and EZH2 cooperate to repress the transcription of miR-101 by binding its promoter.
  • NDY1 upregulation triggers the concerted action of NDY1 and EZH2, leading to increased EZH2 levels and sustained miR-101 repression.
  • FGF-2 induces NDY1 via CREB phosphorylation, mediating cellular effects on proliferation, migration, and angiogenesis.
  • The identified FGF-2-NDY1/EZH2-miR-101-EZH2 axis is active in bladder cancer.

Conclusions:

  • A novel oncogenic pathway involving FGF-2, NDY1, EZH2, and miR-101 has been delineated.
  • This pathway links FGF-2 signaling to EZH2-mediated gene silencing through NDY1 and miR-101.
  • The findings provide insights into the mechanisms of oncogenesis and potential therapeutic targets in bladder cancer.

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