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Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure
Gulfem Dilek Guler1, Charles Albert Tindell1, Robert Pitti1
1Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cancer Cell
|August 8, 2017
Summary
Cancer cells surviving drug treatment, known as drug-tolerant persisters (DTPs), show repressed chromatin with increased histone methylation. This epigenetic state, particularly over LINE-1 elements, is crucial for DTP survival.
Area of Science:
- Epigenetics
- Cancer Biology
- Genomics
Background:
- Phenotypic heterogeneity aids cell population survival under stress.
- Drug-tolerant persisters (DTPs) are cancer cell subpopulations surviving lethal drug treatments.
Purpose of the Study:
- To investigate the epigenetic mechanisms maintaining DTP survival.
- To identify key genomic regions and regulatory factors involved in DTP persistence.
Main Methods:
- Analysis of chromatin states in DTPs, focusing on histone modifications (H3K9me3, H3K27me3).
- Investigating the role of heterochromatin regulators and long interspersed repeat element 1 (LINE-1).
- Experimental disruption of repressive chromatin over LINE-1 elements in DTPs.
Main Results:
- DTPs exhibit a repressed chromatin state with increased H3K9me3 and H3K27me3.
- Survival of DTPs is partly maintained by regulators of H3K9me3-mediated heterochromatin.
- Increased H3K9me3 in DTPs is prominent over LINE-1 elements.
- Disrupting LINE-1 chromatin repression leads to DTP ablation, partially rescued by reducing LINE-1 expression.
Conclusions:
- Epigenetic repression, specifically H3K9me3 over LINE-1 elements, is critical for cancer drug tolerance.
- Targeting LINE-1 elements or their associated repressive chromatin may offer strategies to eliminate DTPs.
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