Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

Int J Cancer. 2020 Mar 1;146(5):1281-1292. doi: 10.1002/ijc.32649. Epub 2019 Oct 11.


Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DNA damage response genes. Upon knockdown of histone demethylases, KDM4C and KDM7A both differentiation and DNA damage were induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

Keywords: DNA repair; cancer stem cells; heterochromatin; histone acetylation; histone methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Self Renewal / genetics
  • Chromatin / metabolism
  • DNA Methylation
  • DNA Repair / genetics
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • HEK293 Cells
  • Histones
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lysine / metabolism
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Promoter Regions, Genetic / genetics
  • RNA, Small Interfering / metabolism
  • Xenograft Model Antitumor Assays


  • Chromatin
  • Histones
  • RNA, Small Interfering
  • Jumonji Domain-Containing Histone Demethylases
  • Lysine