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Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function

Lixin Wan1, Kexin Xu2, Yongkun Wei3

  • 1Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Molecular Cell
|January 21, 2018
PubMed

Insights

AMP-activated protein kinase (AMPK) activates tumor suppression by phosphorylating EZH2, inhibiting cancer cell growth. This finding suggests AMPK agonists could enhance EZH2-targeted cancer therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis.
  • Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator involved in gene silencing and cancer.

Purpose of the Study:

  • To investigate the role of AMPK in regulating EZH2 activity and its impact on cancer.
  • To explore the therapeutic potential of targeting the AMPK-EZH2 pathway in cancer treatment.

Main Methods:

  • Western blotting and immunoprecipitation to assess protein interactions and phosphorylation.
  • Quantitative PCR and RNA sequencing to analyze gene expression.
  • Cell culture and mouse xenograft models to evaluate tumor growth inhibition.
  • Immunohistochemistry to correlate protein levels with patient survival data.

Main Results:

  • AMPK phosphorylates EZH2 at Threonine 311 (T311), disrupting the PRC2 complex by preventing EZH2-SUZ12 interaction.
  • Phosphorylation of T311-EZH2 leads to decreased H3K27 methylation and upregulation of PRC2 target genes, including tumor suppressors.
  • This mechanism suppresses tumor cell proliferation in vitro and in vivo.
  • Clinical analysis shows a positive correlation between AMPK activity, pT311-EZH2 levels, and improved survival in ovarian and breast cancer patients.

Conclusions:

  • AMPK-mediated phosphorylation of EZH2 at T311 acts as a tumor-suppressive mechanism.
  • Elevated pT311-EZH2 is a biomarker for better prognosis in certain cancers.
  • AMPK agonists represent a potential strategy to sensitize tumors to EZH2-targeting therapies.
Keywords:
AMPKEZH2metforminovarian cancerphosphorylationpolycomb repressive complex 2

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