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

Mol Cell. 2018 Jan 18;69(2):279-291.e5. doi: 10.1016/j.molcel.2017.12.024.

Abstract

Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.

Keywords: AMPK; EZH2; metformin; ovarian cancer; phosphorylation; polycomb repressive complex 2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Carcinogenesis / genetics
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Methylation
  • DNA-Binding Proteins / metabolism
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Enhancer of Zeste Homolog 2 Protein / physiology
  • Epigenesis, Genetic
  • Female
  • Histones / metabolism
  • Humans
  • Mice
  • Nuclear Proteins / metabolism
  • Oncogenes
  • Ovarian Neoplasms / metabolism
  • Phosphorylation
  • Polycomb Repressive Complex 2 / metabolism
  • Polycomb Repressive Complex 2 / physiology
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Histones
  • Nuclear Proteins
  • SUZ12 protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • AMP-Activated Protein Kinases