Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Protein Chemistry, Genentech Inc., South San Francisco, CA, USA.
Cancer Cell. 2017 Aug 14;32(2):221-237.e13. doi: 10.1016/j.ccell.2017.07.002. Epub 2017 Aug 3.
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 subpopulation 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.
细胞群体中表型异质性的维持是一种进化上保守的机制，它是细胞在应激暴露下存活的基础。我们表明，在对其他致命药物有耐药性的癌细胞亚群中，存活下来的药物耐受持久细胞（DTP）的基因组表现出抑制性染色质状态，其特征是组蛋白 H3 赖氨酸 9 和 27（H3K9 和 H3K27）的甲基化增加。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剂维持的，并且在 DTP 中观察到的 H3K9me3 增加主要出现在长散布重复元件 1（LINE-1）上。在 DTP 中破坏 LINE-1 元件上的抑制性染色质会导致 DTP 消融，通过降低 LINE-1 的表达或功能可以部分挽救这种消融。
