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

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 DDR genes. Upon knockdown of histone demethylases KDM4C and KDM7A both differentiation and DNA damage was 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.EGA study EGAS00001003750

肿瘤起始细胞（Tumor-initiating cells）是一类具备自我更新能力、可重建肿瘤的细胞亚群。本研究在人胶质母细胞瘤起始细胞（GICs）中鉴定出干细胞样染色质特征，并将此类特征与组蛋白H3赖氨酸9三甲基化（H3K9me3）抑制性标记的丢失建立关联。通过抑制组蛋白去甲基化酶以提升H3K9me3水平，可诱导GICs发生细胞死亡，却不会对其分化后的对应细胞产生杀伤效应。细胞凋亡的诱导过程伴随激活型组蛋白H3赖氨酸9乙酰化（H3K9ac）修饰的丢失、DNA损伤积累以及DNA损伤应答（DDR）基因的表达下调。对组蛋白去甲基化酶KDM4C与KDM7A实施基因敲低后，同样可同时诱导细胞分化与DNA损伤。综上，H3K9me3与H3K9ac的动态平衡对GIC的存活至关重要，该染色质特征可被用于特异性靶向这一肿瘤细胞亚群。本研究为EGA研究项目EGAS00001003750。