Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells

Cancer Cell. 2013 Jun 10;23(6):839-52. doi: 10.1016/j.ccr.2013.04.008. Epub 2013 May 16.


Glioblastoma multiforme (GBM) displays cellular hierarchies harboring a subpopulation of stem-like cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), the lysine methyltransferase of Polycomb repressive complex 2, mediates transcriptional repression of prodifferentiation genes in both normal and neoplastic stem cells. An oncogenic role of EZH2 as a transcriptional silencer is well established; however, additional functions of EZH2 are incompletely understood. Here, we show that EZH2 binds to and methylates STAT3, leading to enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. The EZH2-STAT3 interaction preferentially occurs in GSCs relative to non-stem bulk tumor cells, and it requires a specific phosphorylation of EZH2. Inhibition of EZH2 reverses the silencing of Polycomb target genes and diminishes STAT3 activity, suggesting therapeutic strategies.

Publication types

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

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Silencing
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Methylation
  • Mice
  • Phosphorylation
  • Polycomb Repressive Complex 2 / metabolism
  • Polycomb Repressive Complex 2 / physiology*
  • Polycomb-Group Proteins
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Transplantation, Heterologous
  • Tumor Cells, Cultured


  • Polycomb-Group Proteins
  • STAT3 Transcription Factor
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Proto-Oncogene Proteins c-akt