Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 146, Issue 5, Pages 1281-1292Publisher
WILEY
DOI: 10.1002/ijc.32649
Keywords
cancer stem cells; histone methylation; histone acetylation; heterochromatin; DNA repair
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Funding
- Cooperation Program in Cancer Research of the German Cancer Research Center (DKFZ)
- Israel's Ministry of Science, Technology and Space (MOST) [Ca146, Ca180]
- German CellNetworks Cluster of Excellence [EXC81]
- Anni Hofmann foundation
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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.
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