Epigenetic Repression of LINE-1 Elements Protects Drug-Resistant Cells

A population of largely quiescent drug-tolerant persister (DTP) cells can serve as the founder cells for relapse in patients with cancer. The DTP state is reversible, suggesting the potential for epigenetic mechanisms of regulation, prompting Guler, Tindell, and colleagues to investigate epigenetic mechanisms of DTP survival. In the EGFR-mutant lung cancer cell line, DTPs generated with an EGFR inhibitor displayed alterations in histone H3 marks including an increase in methylation of H3K9 and H3K27 compared with parental cells, and these findings were validated in other cancer cell lines. These changes in histone modifications were not observed prior to drug exposure in the subpopulation that will become DTPs. Consistent with these findings, H3K9 methyltransferases and some H3K27 methyltransferase components were upregulated in DTPs and in patients with drug-resistant BRAF^V600E melanoma. Further, an siRNA screen revealed that genes that promote H3K9me3-mediated heterochromatin formation (such as ATRX, SETDB1, G9a, and several class I HDACs) were required for DTP survival, indicating that H3K9 methylation–dependent heterochromatin formation is required to establish the drug-tolerant state. Consistent with these findings, knockdown or inhibition of the SETDB1 or G9a methyltransferases reduced the number of DTPs. RNA sequencing revealed a drug-induced expression of repeat elements and IFN response/antiviral response genes in the heterogeneous cancer cell population. Mechanistically, H3K9 methylation accumulated at LINE-1 elements in DTPs, preventing their stress-induced expression in response to drug treatment, and promoting DTP survival. HDAC inhibitors disrupted H3K9 methylation–dependent heterochromatin formation, thereby specifically derepressing LINE-1 elements in DTPs. HDAC inhibition also promoted selected cell death of DTPs, which could be partially rescued by suppressing LINE-1 element expression and function. The finding that DTPs are maintained in part by repressive chromatin at LINE-1 elements suggests the possibility of using H3K9 methyltransferase inhibitors or other epigenetic inhibitors to selectively target DTPs to reduce drug resistance in cancer.

Guler GD, Tindell CA, Pitti R, Wilson C, Nichols K, KaiWai Cheung T, et al. Repression of stress-induced LINE-1 expression protects cancer cell subpopulations from lethal drug exposure. Cancer Cell 2017 Jul 24 [Epub ahead of print].

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