Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure

Publication date: Available online 3 August 2017
Source:Cancer Cell
Author(s): Gulfem Dilek Guler, Charles Albert Tindell, Robert Pitti, Catherine Wilson, Katrina Nichols, Tommy KaiWai Cheung, Hyo-Jin Kim, Matthew Wongchenko, Yibing Yan, Benjamin Haley, Trinna Cuellar, Joshua Webster, Navneet Alag, Ganapati Hegde, Erica Jackson, Tracy Leah Nance, Paul Garrett Giresi, Kuan-Bei Chen, Jinfeng Liu, Suchit Jhunjhunwala, Jeff Settleman, Jean-Philippe Stephan, David Arnott, Marie Classon
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.

Graphical abstract

Teaser

Guler et al. show that drug-tolerant persisters (DTPs), a cancer cell subpopulation surviving lethal drugs, are partly maintained by a repressed chromatin state, prominently at LINE-1 elements. Disrupting the repressive chromatin results in death of DTPs, which is partially rescued by reducing LINE-1 expression.


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