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

Lixin Wan, Kexin Xu, Yongkun Wei, Jinfang Zhang, Tao Han, Christopher Fry, Zhao Zhang, Yao Vickie Wang, Liyu Huang, Min Yuan, Weiya Xia, Wei Chao Chang, Wen Chien Huang, Chien Liang Liu, Yuan Ching Chang, Jinsong Liu, Yun Wu, Victor X. Jin, Xiangpeng Dai, Jianfeng GuoJia Liu, Shulong Jiang, Jin Li, John M. Asara, Myles Brown, Mien Chie Hung, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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. The metabolic state of the cell can be connected to gene expression and modification of histones through several mechanisms. Wan et al. find that AMPK-mediated phosphorylation of EZH2 at T311 inhibits PRC2 methyltransferase activity to relieve PRC2-dependent epigenetic silencing and subsequently suppresses tumorigenesis.

Original languageEnglish (US)
Pages (from-to)279-291.e5
JournalMolecular Cell
Volume69
Issue number2
DOIs
StatePublished - Jan 18 2018

Keywords

  • AMPK
  • EZH2
  • metformin
  • ovarian cancer
  • phosphorylation
  • polycomb repressive complex 2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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