Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Nat Chem Biol. 2015 Jul;11(7):472-80. doi: 10.1038/nchembio.1811. Epub 2015 May 11.
Many anticancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors additionally cause histone eviction. Here, we performed genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II (TopoI and II) inhibitors and integrated this mapping with established maps of genomic or epigenomic features to show their activities in different genomic regions. The TopoI inhibitor topotecan and the TopoII inhibitor etoposide are similar in inducing DNA damage at transcriptionally active genomic regions. The anthracycline daunorubicin induces DNA breaks and evicts histones from active chromatin, thus quenching local DNA damage responses. Another anthracycline, aclarubicin, has a different genomic specificity and evicts histones from H3K27me3-marked heterochromatin, with consequences for diffuse large B-cell lymphoma cells with elevated levels of H3K27me3. Modifying anthracycline structures may yield compounds with selectivity for different genomic regions and activity for different tumor types.
许多抗癌药物通过诱导 DNA 断裂来消除肿瘤细胞。蒽环类拓扑异构酶 II 抑制剂还会导致组蛋白排出。在这里，我们对各种拓扑异构酶 I 和 II（TopoI 和 TopoII）抑制剂的化疗效果进行了全基因组高分辨率作图，并将该作图与已建立的基因组或表观基因组特征图谱进行了整合，以显示它们在不同基因组区域的活性。拓扑异构酶 I 抑制剂拓扑替康和拓扑异构酶 II 抑制剂依托泊苷在诱导转录活跃的基因组区域的 DNA 损伤方面相似。蒽环类药物柔红霉素诱导 DNA 断裂并从活性染色质中排出组蛋白，从而抑制局部 DNA 损伤反应。另一种蒽环类药物阿克拉霉素具有不同的基因组特异性，从 H3K27me3 标记的异染色质中排出组蛋白，对 H3K27me3 水平升高的弥漫性大 B 细胞淋巴瘤细胞产生影响。修饰蒽环类药物的结构可能会产生对不同基因组区域具有选择性和对不同肿瘤类型具有活性的化合物。
