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

Jan Philipp Mallm*, Paul Windisch, Alva Biran, Zoltan Gal, Sabrina Schumacher, Rainer Glass, Christel Herold-Mende, Eran Meshorer, Martje Barbus, Karsten Rippe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1281-1292
Number of pages12
JournalInternational Journal of Cancer
Volume146
Issue number5
DOIs
StatePublished - 1 Mar 2020

Bibliographical note

Publisher Copyright:
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

Keywords

  • DNA repair
  • cancer stem cells
  • heterochromatin
  • histone acetylation
  • histone methylation

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