title: Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells.
abstract: 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.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.forename: Misuk
authors.initials: M
authors.lastname: Kim
authors.forename: Dong-Hun
authors.initials: DH
authors.lastname: Woo
authors.forename: Yongjae
authors.initials: Y
authors.lastname: Shin
authors.forename: Jihye
authors.initials: J
authors.lastname: Shin
authors.forename: Nakho
authors.initials: N
authors.lastname: Chang
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Oh
authors.forename: Hong
authors.initials: H
authors.lastname: Kim
authors.forename: Jingeun
authors.initials: J
authors.lastname: Rheey
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D000071221:Enhancer of Zeste Homolog 2 Protein; D020868:Gene Silencing; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008745:Methylation; D051379:Mice; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism / Q000502:physiology*; D063146:Polycomb-Group Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D063146:Polycomb-Group Proteins; D050796:STAT3 Transcription Factor; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D051057:Proto-Oncogene Proteins c-akt