Related Experiment Video
Updated: Sep 27, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
H3K27me3 conditions chemotolerance in triple-negative breast cancer
Justine Marsolier1,2, Pacôme Prompsy1,2, Adeline Durand1,2
1CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Abstract:
The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages with single-cell resolution, we show that the repressive histone mark H3K27me3 (trimethylation of histone H3 at lysine 27) regulates cell fate at the onset of chemotherapy. We report that a persister expression program is primed with both H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation. We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy. Conversely, preventing H3K27me3 demethylation simultaneously to chemotherapy inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo. Our results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy.
Insights
Histone mark H3K27me3 controls chemotherapy resistance in triple-negative breast cancer. Modulating this epigenetic mark can enhance drug tolerance or delay tumor recurrence, offering new therapeutic strategies.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Therapy resistance in triple-negative breast cancer (TNBC) leads to high recurrence rates.
- Mechanisms driving non-genetic drug tolerance in cancer are poorly understood.
- Epigenetic modifications play a crucial role in cellular plasticity and treatment response.
Purpose of the Study:
- To investigate the role of histone modifications in chemotherapy resistance.
- To identify epigenetic regulators of drug tolerance in TNBC.
- To explore therapeutic strategies targeting chromatin states for improved cancer treatment.
Main Methods:
- Single-cell epigenome and transcriptome profiling.
- Analysis of histone modifications, including H3K27me3 and H3K4me3.
- In vivo studies in mouse models to assess tumor recurrence.
Main Results:
- The repressive histone mark H3K27me3 regulates cell fate during chemotherapy onset.
- A persister expression program is primed by H3K4me3 and H3K27me3, with H3K27me3 acting as a transcriptional 'lock'.
- Depleting H3K27me3 increases chemotherapy tolerance, while inhibiting its demethylation delays drug tolerance and tumor recurrence.
Conclusions:
- Chromatin landscapes, specifically H3K27me3, critically shape cancer cell responses to initial therapy.
- Targeting H3K27me3 demethylation presents a promising strategy to overcome chemotherapy resistance.
- Understanding epigenetic regulation of drug tolerance can lead to novel therapeutic interventions for TNBC.
Related Concept Videos
02:17The Tumor Microenvironment
01:27Chemotaxis in E. coli
01:21Chemotaxis and Direction of Cell Migration
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...