Hong Yu, Li Xinlan, Li Jia, He Qiuyi, Huang Manbing, Tang Yubo, Chen Xiao, Chen Jie, Tang Ke-Jing, Wei Chao
Department of Pharmacy, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Clin Epigenetics. 2024 Jul 16;16(1):91. doi: 10.1186/s13148-024-01709-8.
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.
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.
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.
阿霉素（Dox）是一种对多种癌症有效的化疗药物，但其临床应用受到严重心脏毒性的限制。Dox治疗可在转录水平激活心肌细胞中多个与心脏毒性相关的基因，然而这种整体基因激活的潜在机制仍知之甚少。
在此，我们整合了来自动物模型、Dox治疗后的CUT&Tag和RNA测序数据，发现Dox治疗后心肌细胞中H3K27ac（一种与基因激活相关的组蛋白修饰）水平显著升高。组蛋白乙酰转移酶抑制剂C646可逆转Dox诱导的心肌细胞中H3K27ac积累，随后防止Dox诱导的DNA损伤和细胞凋亡增加。此外，C646通过恢复射血分数和逆转缩短分数百分比，减轻了Dox治疗小鼠的心脏功能障碍。另外，Dox治疗增加了包括Bax、Fas和Bnip3在内的多个心脏毒性基因启动子处的H3K27ac沉积，导致它们上调。此外，H3K27ac在心脏毒性相关基因上的沉积在全基因组中呈现出广泛的特征。基于H3K27ac的沉积和mRNA表达水平，预测了几个可能导致Dox诱导的心脏毒性的潜在基因。最后，Dox治疗后H3K27ac调节的心脏毒性基因的上调在物种间具有保守性。
综上所述，Dox诱导的表观遗传修饰，特别是H3K27ac，作为激活与严重心脏毒性相关基因的分子开关，导致心肌细胞死亡和心脏功能障碍。这些发现为Dox诱导的心脏毒性与表观遗传调控之间的关系提供了新的见解，并确定H3K27ac为预防和治疗Dox诱导的心脏毒性的潜在靶点。
