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Updated: Jun 21, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
H3K27ac acts as a molecular switch for doxorubicin-induced activation of cardiotoxic genes
Yu Hong1, Xinlan Li1,2, Jia Li1
1Department of Pharmacy, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Background:
Doxorubicin (Dox) is an effective chemotherapeutic drug for various cancers, but its clinical application is limited by severe cardiotoxicity. Dox treatment can transcriptionally activate multiple cardiotoxicity-associated genes in cardiomyocytes, the mechanisms underlying this global gene activation remain poorly understood.
Methods And Results:
Herein, we integrated data from animal models, CUT&Tag and RNA-seq after Dox treatment, and discovered that the level of H3K27ac (a histone modification associated with gene activation) significantly increased in cardiomyocytes following Dox treatment. C646, an inhibitor of histone acetyltransferase, reversed Dox-induced H3K27ac accumulation in cardiomyocytes, which subsequently prevented the increase of Dox-induced DNA damage and apoptosis. Furthermore, C646 alleviated cardiac dysfunction in Dox-treated mice by restoring ejection fraction and reversing fractional shortening percentages. Additionally, Dox treatment increased H3K27ac deposition at the promoters of multiple cardiotoxic genes including Bax, Fas and Bnip3, resulting in their up-regulation. Moreover, the deposition of H3K27ac at cardiotoxicity-related genes exhibited a broad feature across the genome. Based on the deposition of H3K27ac and mRNA expression levels, several potential genes that might contribute to Dox-induced cardiotoxicity were predicted. Finally, the up-regulation of H3K27ac-regulated cardiotoxic genes upon Dox treatment is conservative across species.
Conclusions:
Taken together, Dox-induced epigenetic modification, specifically H3K27ac, acts as a molecular switch for the activation of robust cardiotoxicity-related genes, leading to cardiomyocyte death and cardiac dysfunction. These findings provide new insights into the relationship between Dox-induced cardiotoxicity and epigenetic regulation, and identify H3K27ac as a potential target for the prevention and treatment of Dox-induced cardiotoxicity.
Insights
Doxorubicin (Dox) causes heart damage by activating genes through H3K27ac epigenetic changes. Inhibiting this modification protects against Dox-induced cardiotoxicity and cardiac dysfunction.
Area of Science:
- Cardiovascular Research
- Epigenetics
- Molecular Biology
Background:
- Doxorubicin (Dox) is a potent chemotherapy drug with dose-limiting cardiotoxicity.
- Mechanisms of Dox-induced global gene activation in cardiomyocytes are not fully understood.
Purpose of the Study:
- Investigate the role of epigenetic modifications in Dox-induced cardiotoxicity.
- Identify potential therapeutic targets to mitigate Dox-induced heart damage.
Main Methods:
- Integrated animal models, CUT&Tag, and RNA-seq analyses.
- Assessed H3K27ac levels and gene expression post-Dox treatment.
- Utilized C646, a histone acetyltransferase inhibitor.
Main Results:
- Dox treatment significantly increased H3K27ac levels in cardiomyocytes.
- C646 reversed Dox-induced H3K27ac accumulation, DNA damage, and apoptosis.
- C646 treatment improved cardiac function in Dox-treated mice.
- H3K27ac deposition at cardiotoxic gene promoters (e.g., Bax, Fas, Bnip3) correlated with their upregulation.
- H3K27ac-mediated gene activation is conserved across species.
Conclusions:
- Dox-induced H3K27ac acts as a molecular switch for cardiotoxic gene activation.
- Epigenetic regulation via H3K27ac contributes to cardiomyocyte death and cardiac dysfunction.
- H3K27ac is a promising therapeutic target for preventing and treating Dox-induced cardiotoxicity.
