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

E Kim, M Kim, DH Woo, Y Shin, J Shin, N Chang… - Cancer cell, 2013 - cell.com
E Kim, M Kim, DH Woo, Y Shin, J Shin, N Chang, YT Oh, H Kim, J Rheey, I Nakano, C Lee
Cancer cell, 2013cell.com
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 …
Summary
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.
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