title: Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis.
abstract: 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 theNOTCH1promoter. 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.
authors.affiliation: Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Pang
authors.affiliation: Department of Histology and Embryology, Shandong University School of Medicine, Jinan, 250012, Shandong, China.
authors.forename: Guangyan
authors.initials: G
authors.lastname: Gu
authors.affiliation: Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.
authors.forename: Taihong
authors.initials: T
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Department of Histology and Embryology, Shandong University School of Medicine, Jinan, 250012, Shandong, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008550:Melatonin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D008550:Melatonin
keywords: EZH2; Glioblastoma stem-like cells; Melatonin; NOTCH1; self-renewal; viability