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Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to loss of DNA repair capacity

ABSTRACT: Cancer stem cells are characterized by their self-renewal properties and their ability to regenerate a tumor. They have chromatin features that are reminiscent of embryonic stem cells. Here, we link these stem cell-like characteristics of human glioblastoma initiating cells (GICs) to a loss of heterochromatin features. Increased histone H3 lysine 9 trimethylation (H3K9me3) levels due to histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by the accumulation of DNA double-strand breaks. By ChIP-seq and RNA-seq analysis we found that DNA repair genes of the ATM and ATR pathway lost the active H3 lysine 9 acetylation (H3K9ac) and were downregulated upon knockdown of the histone demethylases KDM4C and KDM7A, while regulators of neuron differentiation were up-regulated. Thus, the H3K9me3-H3K9ac equilibrium is a crucial feature for maintaining the stemness in GICs and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122832 | GEO | 2020/03/02

REPOSITORIES: GEO

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

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