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

Autor: Mallm JP; Division of Chromatin Networks, German Cancer Research Center (DKFZ), Heidelberg, Germany., Windisch P; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Biran A; Department of Genetics, Institute of Life Sciences, and the Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Jerusalem, Israel., Gal Z; Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany., Schumacher S; Division of Chromatin Networks, German Cancer Research Center (DKFZ), Heidelberg, Germany., Glass R; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Herold-Mende C; Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany., Meshorer E; Department of Genetics, Institute of Life Sciences, and the Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Jerusalem, Israel., Barbus M; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Rippe K; Division of Chromatin Networks, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2020 Mar 01; Vol. 146 (5), pp. 1281-1292. Date of Electronic Publication: 2019 Oct 11.
DOI: 10.1002/ijc.32649
Abstrakt: 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.
(© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
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