Division of Chromatin Networks, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Int J Cancer. 2020 Mar 1;146(5):1281-1292. doi: 10.1002/ijc.32649. Epub 2019 Oct 11.
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.
肿瘤起始细胞是一类具有自我更新能力以再生肿瘤的细胞亚群。在这里，我们在人神经胶质瘤起始细胞 (GIC) 中鉴定出类似干细胞的染色质特征，并将其与抑制性组蛋白 H3 赖氨酸 9 三甲基化 (H3K9me3) 标记的丧失联系起来。通过组蛋白去甲基酶抑制增加 H3K9me3 水平会导致 GIC 死亡，但不会导致其分化对应的细胞死亡。凋亡的诱导伴随着激活的 H3 赖氨酸 9 乙酰化 (H3K9ac) 修饰的丧失、DNA 损伤的积累和 DNA 损伤反应基因的下调。在敲低组蛋白去甲基酶后，KDM4C 和 KDM7A 均诱导分化和 DNA 损伤。因此，H3K9me3-H3K9ac 平衡对于 GIC 的存活至关重要，并且代表了一种可以被利用来特异性靶向该肿瘤亚群的染色质特征。
