Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure
Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure
复制标题
DOI：
10.1016/j.ccell.2017.07.002
复制
发表时间：
2017-08-14
期刊：
影响因子：
50.3
通讯作者：
Classon, Marie
中科院分区：
文献类型：
--
作者：
Guler, Gulfem Dilek;Tindell, Charles Albert;Classon, Marie
细胞群体内表型异质性的维持是一种进化上保守的机制，是群体在压力下生存的基础。我们发现，在用其他致命药物（DTP）治疗后存活下来的癌细胞亚群的基因组表现出染色质抑制状态，其特征是组蛋白 H3 赖氨酸 9 和 27（H3K9 和 H3K27）甲基化增加。我们还表明，DTP 的存活部分是由 H3K9me3 介导的异染色质形成的调节因子维持的，并且观察到的 DTP 中 H3K9me3 的增加在长散布重复元件 1 (LINE-1) 上最为显着。 DTP 中 LINE-1 元件上的抑制性染色质的破坏会导致 DTP 消融，这可以通过减少 LINE-1 表达或功能来部分挽救。
Maintenance of phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that underlies population survival upon stressful exposures. We show that the genomes of a cancer cell sub population that survives treatment with otherwise lethal drugs, the drug-tolerant persisters (DTPs), exhibit a repressed chromatin state characterized by increased methylation of histone H3 lysines 9 and 27 (H3K9 and H3K27). We also show that survival of DTPs is, in part, maintained by regulators of H3K9me3-mediated heterochromatin formation and that the observed increase in H3K9me3 in DTPs is most prominent over long interspersed repeat element 1 (LINE-1). Disruption of the repressive chromatin over LINE-1 elements in DTPs results in DTP ablation, which is partially rescued by reducing LINE-1 expression or function.