Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis.
Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis.
复制标题
褪黑素通过抑制 EZH2-NOTCHI 信号轴抑制胶质母细胞瘤干细胞
DOI：
10.7150/ijbs.16818
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发表时间：
2017
影响因子：
9.2
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Zheng X;Pang B;Gu G;Gao T;Zhang R;Pang Q;Liu Q
胶质母细胞瘤干细胞样细胞（GSC）在胶质瘤生长、放射和化学抗性以及复发中起重要作用。因此，GSC的消除已成为胶质母细胞瘤治疗中的关键策略和挑战。在这里，我们表明，褪黑激素，吲哚胺来自I-色氨酸，显着抑制活力和自我更新能力的GSC伴随着干细胞标志物的减少。我们已经确定EZH 2-NOTCH 1信号传导是调节褪黑激素在GSC中作用的关键信号通路。EZH 2不是通过在组蛋白3的赖氨酸27（H3 K27）处产生甲基化的表观遗传标记来转录沉默基因表达，而是通过直接结合NOTCH 1启动子来调节NOTCH 1表达。此外，在临床肿瘤样品中观察到EZH 2和NOTCH胞内结构域1（NICD 1）的表达之间的相关性，明显支持在胶质瘤和GSC中存在EZH 2-NOTCH 1相互作用。总的来说，我们证明了褪黑激素，一种潜在的肿瘤抑制剂，通过EZH 2-NOTCH 1信号轴抑制GSC特性部分地执行其功能。
Glioblastoma stem-like cells (GSCs) play essential roles in glioma growth, radio- and chemo-resistance, and recurrence. Elimination of GSCs has therefore become a key strategy and challenge in glioblastoma therapy. Here, we show that melatonin, an indolamine derived from I-tryptophan, significantly inhibited viability and self-renewal ability of GSCs accompanied by a decrease of stem cell markers. We have identified EZH2-NOTCH1 signaling as the key signal pathway that regulated the effects of melatonin in the GSCs. Instead of transcriptionally silencing gene expression by generating a methylated epigenetic mark at histone 3 at lysine 27 (H3K27), EZH2 regulates NOTCH1 expression by directly binding to the NOTCH1 promoter. Moreover, correlation between the expressions of EZH2 and NOTCH intracellular domain 1 (NICD1) was observed in the clinical tumor samples, evidently supporting the existence of EZH2-NOTCH1 interaction in the gliomas and GSCs. Collectively, we demonstrated that melatonin, a potential tumor inhibitor, performs its function partly by suppressing GSC properties through EZH2-NOTCH1 signaling axis.