Zheng Xiangrong, Pang Bo, Gu Guangyan, Gao Taihong, Zhang Rui, Pang Qi, Liu Qian
Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.
Int J Biol Sci. 2017 Feb 6;13(2):245-253. doi: 10.7150/ijbs.16818. eCollection 2017.
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 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.
胶质母细胞瘤干细胞（GSCs）在胶质瘤的生长、放疗和化疗抗性以及复发中起着至关重要的作用。因此，消除GSCs已成为胶质母细胞瘤治疗的关键策略和挑战。在此，我们表明，褪黑素，一种由L-色氨酸衍生的吲哚胺，显著抑制了GSCs的活力和自我更新能力，并伴随着干细胞标志物的减少。我们已确定EZH2-NOTCH1信号通路是调节褪黑素对GSCs作用的关键信号通路。EZH2并非通过在组蛋白3赖氨酸27（H3K27）处产生甲基化表观遗传标记来转录沉默基因表达，而是通过直接结合启动子来调节NOTCH1的表达。此外，在临床肿瘤样本中观察到EZH2与NOTCH细胞内结构域1（NICD1）表达之间的相关性，明显支持了EZH2-NOTCH1相互作用在胶质瘤和GSCs中的存在。总体而言，我们证明了褪黑素，一种潜在的肿瘤抑制剂，部分通过EZH2-NOTCH1信号轴抑制GSC特性来发挥其功能。
