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

Abstract

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.

Drug persistence – From antibiotics to cancer therapies

“…Expression of EMT/stem-cell markers is a frequent hallmark of persister subpopulations, which can be exploited to isolate persister cells within isogenic populations [30,31,35,36,45]. Second, several lines of evidence point towards chromatin remodeling as a key step in persister formation [2,32,46,47]. For example, inhibition of the histone demethylases KDM5 and KDM6 were found to suppress the emergence of persisters [35,46].…”

Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

“…These two miRNAs belong to the same family and are structurally related. Intriguingly, the panobinostat treatment (43). In the present study, we primarily focused on regions with a decreased H3K27ac signal following acquired resistance, but regions with a higher H3K27ac signal were also observed.…”

The impact of non-genetic heterogeneity on cancer cell death

“…At the molecular level, gefitinib-induced PC9 DTPs are characterized by widespread alterations in histone modification, including a global decrease in histone 3 lysine acetylation (H3KAc), reduced trimethylation of H3K4 and increased H3K9 and H3K27 methylation (Guler et al 2017). Changes in histone modifications correlate with increased expression of lysine demethylase 5A (KDM5A), which removes methyl groups from H3K4, as well as SETDB1, which promotes H3K9 methylation (Sharma et al 2010; Guler et al 2017).…”

“…Changes in histone modifications correlate with increased expression of lysine demethylase 5A (KDM5A), which removes methyl groups from H3K4, as well as SETDB1, which promotes H3K9 methylation (Sharma et al 2010; Guler et al 2017). Interestingly, the lysine demethylase KDM5B is enriched in drug tolerant melanoma cells exposed to the BRAF inhibitor vemurafenib (Roesch et al 2013), while glioblastoma stem cells tolerant of tyrosine kinase inhibitors require KDM6A/B function (Liau et al 2017), implicating altered lysine methylation in the establishment and maintenance of the DTP state in diverse models.…”

“…Another possibility is that the epigenetic modifications observed in DTPs (e.g. H3K9 methylation) may function to globally repress the expression of long interspersed repeat elements (LINEs) (Guler et al 2017). LINE expression is increased by drug treatment, but how repressing LINE expression contributes to the DTP state, and how LINE expression might contribute to drug induced cell death in sensitive parental cells, remains to be fully explored.…”