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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Dephosphorylation-induced EZH2 activation mediated RECK downregulation by ERK1/2 signaling

Shilong Ning1, Xiao Ma2

  • 1Department of Clinical Nutrition, Jinhua Municipal Central Hospital, Jinhua, China.

Journal of Cellular Physiology
|March 27, 2019
PubMed

Insights

The enhancer of zeste homolog 2 (EZH2) enzyme epigenetically silences the RECK gene, a cancer inhibitor, by promoting H3K27 trimethylation. Extracellular signal-related kinases (ERK)-1/2 signaling further enhances this silencing mechanism.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene inhibits cancer metastasis and angiogenesis.
  • RECK expression is often downregulated in progressing cancers, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the epigenetic mechanisms regulating RECK expression.
  • To investigate the role of enhancer of zeste homolog 2 (EZH2) and extracellular signal-related kinases (ERK)-1/2 signaling in RECK dysregulation.

Main Methods:

  • Chromatin immunoprecipitation assays to assess H3K27 trimethylation at the RECK promoter.
  • Western blotting to detect protein levels and phosphorylation.
  • In vitro assays to determine EZH2 activity modulation.

Main Results:

  • EZH2 directly attenuates RECK expression by catalyzing H3K27 trimethylation on the RECK promoter.
  • ERK1/2 signaling enhances EZH2 activity, leading to increased H3K27 trimethylation and RECK suppression.
  • Posttranslational phosphorylation of EZH2 at serine-21 by ERK1/2 is crucial for this regulatory process.

Conclusions:

  • EZH2 epigenetically represses RECK expression via H3K27 trimethylation.
  • The ERK1/2 pathway modulates EZH2 activity, contributing to RECK downregulation in cancer progression.
Keywords:
ERK1/2EZH2H3K27me3RECK

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