Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis

Int J Biol Sci. 2017 Feb 6;13(2):245-253. doi: 10.7150/ijbs.16818. eCollection 2017.

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 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.

Keywords: EZH2; Glioblastoma stem-like cells; Melatonin; NOTCH1; self-renewal; viability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Chromatin Immunoprecipitation
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Glioblastoma / metabolism*
  • Humans
  • Immunohistochemistry
  • Melatonin / pharmacology*
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism*
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • NOTCH1 protein, human
  • Receptor, Notch1
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Melatonin