Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure
Open accessAbstract
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.
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Cells may survive initial drug treatment by epigenetic adaptations that enable a drug-tolerant, slow-cycling phenotype that precedes the emergence of permanent drug resistance.
“Alternatively, cells may survive initial drug treatment by epigenetic adaptations that enable a drug-tolerant, slow-cycling phenotype that precedes the emergence of permanent drug resistance [23,24].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [24]
The repressive chromatin landscape of EGFR-mutant NSCLC persisters results from histone modifications orchestrated by multiple histone methyltransferases and HDACs including SETDB1, G9a, EZH2, HP1, ATRX, and class I HDACs.
“Subsequent studies by this same group extended these findings to show that the repressive chromatin landscape of EGFR-mutant NSCLC persisters results from histone modifications orchestrated by the action of multiple histone methyltransferases and HDACs including SETDB1, G9a, EZH2, HP1, ATRX, and class I HDACs [24].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [24]
Genetic knockdown of genes that promote H3K9me3-mediated heterochromatin formation decreased persister survival, indicating that H3K9 methylation-dependent heterochromatin formation is required to establish the drug-tolerant state.
“Genetic knockdown of genes that promote H3K9me3-mediated heterochromatin formation (such as ATRX, SETDB1, G9a, and several class I HDACs) decreased persister survival, indicating that H3K9 methylation–dependent heterochromatin formation is required to establish the drug-tolerant state.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [24]
Targeted therapies such as EGFR inhibitors and CDK4/6 inhibitors can induce a strong reactivation of repeated elements in cancer cells, which results in cell death.
“Interestingly, targeted therapies such as EGFR inhibitors and CDK4/6 inhibitors can induce a strong reactivation of repeated elements in cancer cells, which results in cell death [24,102].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [24]
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References 76 · Cited by 277
- Authors
- Guler, G. D., Tindell, C. A., Pitti, R., Wilson, C., Nichols, K., KaiWai Cheung, T., Kim, H.-J., Wongchenko, M., Yan, Y., Haley, B., Cuellar, T., Webster, J., Alag, N., Hegde, G., Jackson, E., Nance, T. L., Giresi, P. G., Chen, K.-B., Liu, J., Jhunjhunwala, S., Settleman, J., Stephan, J.-P., Arnott, D., & Classon, M.
- Affiliations
- Genentech (US)
- Active Motif (United States) (US)
- Corresponding author
- Classon, Marie
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 32
- Issue
- 2
- Pages
- 221-237.e13
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2745178135
- Cited by
- 277
- References
- 76
- Citations by year
- 2026: 30 · 2025: 36 · 2024: 30 · 2023: 30 · 2022: 33 · 2021: 50 · 2020: 33 · 2019: 17 · 2018: 11 · 2017: 6
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- IHC
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- drug-tolerant persisters, LINE-1, heterochromatin, H3K9me3, H3K27 methylation, chromatin repression, stress-responsive gene expression, drug resistance, epigenetic silencing
- MeSH terms
- Animals, Antineoplastic Agents, Chromatin, Histones, Humans, Methylation, Mice, Nude, Neoplasms, Histone-Lysine N-Methyltransferase, Stress, Physiological, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Mice, SCID, Drug Resistance, Neoplasm, Long Interspersed Nucleotide Elements, Xenograft Model Antitumor Assays, Genomic Instability, Mice, Epigenetic Repression
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