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Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation
Author(s) -
Mallm JanPhilipp,
Windisch Paul,
Biran Alva,
Gal Zoltan,
Schumacher Sabrina,
Glass Rainer,
HeroldMende Christel,
Meshorer Eran,
Barbus Martje,
Rippe Karsten
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32649
Subject(s) - demethylase , epigenetics , glioblastoma , histone , cancer research , biology , medicine , neuroscience , genetics , gene
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.