Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
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.
多形性胶质母细胞瘤 (GBM) 表现出细胞层次结构，其中包含一小部分干细胞样细胞 (GSCs)。EZH2 是 Polycomb 抑制复合物 2 的赖氨酸甲基转移酶，它介导正常和肿瘤干细胞中分化前基因的转录抑制。EZH2 作为转录沉默剂的致癌作用已得到充分证实；然而，EZH2 的其他功能尚不完全清楚。在这里，我们表明 EZH2 与 STAT3 结合并使其甲基化，导致 STAT3 活性增强，酪氨酸磷酸化增加。EZH2-STAT3 相互作用优先发生在 GSCs 中，而不是非干细胞的肿瘤细胞中，并且需要 EZH2 的特定磷酸化。抑制 EZH2 可逆转 Polycomb 靶基因的沉默并降低 STAT3 活性，提示治疗策略。
