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

Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells.
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DOI:
10.1016/j.ccr.2013.04.008
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发表时间:
2013-06-10
期刊:
影响因子:
50.3
通讯作者:
Lee J
Lee J
中科院分区:
医学1区
文献类型:
--
作者:
Kim E;Kim M;Woo DH;Shin Y;Shin J;Chang N;Oh YT;Kim H;Rheey J;Nakano I;Lee C;Joo KM;Rich JN;Nam DH;Lee J

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多形性胶质母细胞瘤(GBM)显示含有干细胞样细胞(GSC)亚群的细胞层级。Zeste同源物2增强子(EZH2),Polycomb抑制复合物2的赖氨酸甲基转移酶,介导正常和肿瘤干细胞中促分化基因的转录抑制。EZH2作为转录沉默子的致癌作用已得到充分证实;然而,EZH2的其他功能尚未完全了解。在这里,我们表明EZH2结合并甲基化STAT3,通过增加STAT3的酪氨酸磷酸化而导致STAT3活性增强。EZH2-STAT3相互作用相对于非干大块肿瘤细胞优先发生在GSC中,并且它需要EZH2的特异性磷酸化。EZH2的抑制逆转Polycomb靶基因的沉默并降低STAT3活性,这表明了治疗策略。
Glioblastoma multiforme (GBM) displays cellular hierarchies harboring a subpopulation of stem-like cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), the lysine methyl transferase of Polycomb repressive complex 2, mediates transcriptional repression of pro-differentiation 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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