HDAC and MAPK/ERK Inhibitors Cooperate To Reduce Viability and Stemness in Medulloblastoma

J Mol Neurosci. 2020 Jun;70(6):981-992. doi: 10.1007/s12031-020-01505-y. Epub 2020 Feb 13.

Abstract

Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression of BMI1 and CD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.

Keywords: Brain tumor; Extracellular-regulated kinase; Histone deacetylase; Medulloblastoma; Stem cells.

MeSH terms

  • AC133 Antigen / genetics
  • AC133 Antigen / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Medulloblastoma / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / physiology
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Tumor Cells, Cultured

Substances

  • AC133 Antigen
  • Antineoplastic Agents
  • BMI1 protein, human
  • Histone Deacetylase Inhibitors
  • PROM1 protein, human
  • Protein Kinase Inhibitors
  • Polycomb Repressive Complex 1
  • Mitogen-Activated Protein Kinases