Melatonin inhibits tumorigenicity of glioblastoma stem-like cells via the AKT-EZH2-STAT3 signaling axis

J Pineal Res. 2016 Sep;61(2):208-17. doi: 10.1111/jpi.12341. Epub 2016 Jun 4.


Glioblastoma stem-like cells (GSCs) displaying self-renewing and tumor-propagating capacity play a particularly important role in maintaining tumor growth, therapeutic resistance, and tumor recurrence. Therefore, new therapeutic strategies focusing on impairing GSC maintenance are urgently needed. Here, we used GSCs isolated from surgical specimens from patients with glioblastoma multiforme (GBM) to study the roles and underlying mechanisms associated with melatonin in GSC biology. The results showed that melatonin directly targeted glioma tumor cells by altering GSC biology and inhibiting GSC proliferation. Additionally, melatonin altered profile of transcription factors to inhibit tumor initiation and propagation. Furthermore, EZH2 S21 phosphorylation and EZH2-STAT3 interaction in GSCs were impaired following melatonin treatment. These results suggested that melatonin attenuated multiple key signals involved in GSC self-renewal and survival, and further supported melatonin as a promising GBM therapeutic.

Keywords: EZH2 phosphorylation; EZH2-STAT3 interaction; glioblastoma stem-like cells; melatonin.

MeSH terms

  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Melatonin / pharmacology*
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured


  • STAT3 Transcription Factor
  • STAT3 protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Proto-Oncogene Proteins c-akt
  • Melatonin