MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

Mol Cancer Res. 2017 Sep;15(9):1275-1286. doi: 10.1158/1541-7786.MCR-17-0105. Epub 2017 May 23.


Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK- or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stem-like cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma. Mol Cancer Res; 15(9); 1275-86. ©2017 AACR.

MeSH terms

  • Adolescent
  • Animals
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / metabolism*
  • Cerebellar Neoplasms / pathology
  • Child
  • Child, Preschool
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein / biosynthesis
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Female
  • Heterografts
  • Humans
  • Male
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism*
  • Medulloblastoma / pathology
  • Mice
  • Mice, Inbred BALB C
  • Naphthyridines / pharmacology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / biosynthesis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Random Allocation
  • Tumor Cells, Cultured


  • 1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone
  • Naphthyridines
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • MELK protein, human
  • Protein Serine-Threonine Kinases