文章：

组蛋白与DNA甲基化作为胃癌DNA损伤修复的表观遗传调控因子及新兴治疗机遇

Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities

原文发布日期：13 October 2023

DOI: 10.3390/cancers15204976

类型: Article

开放获取: 是

英文摘要：

Gastric cancer (GC), one of the most common malignancies worldwide, is a heterogeneous disease developing from the accumulation of genetic and epigenetic changes. One of the most critical epigenetic alterations in GC is DNA and histone methylation, which affects multiple processes in the cell nucleus, including gene expression and DNA damage repair (DDR). Indeed, the aberrant expression of histone methyltransferases and demethylases influences chromatin accessibility to the DNA repair machinery; moreover, overexpression of DNA methyltransferases results in promoter hypermethylation, which can suppress the transcription of genes involved in DNA repair. Several DDR mechanisms have been recognized so far, with homologous recombination (HR) being the main pathway involved in the repair of double-strand breaks. An increasing number of defective HR genes are emerging in GC, resulting in the identification of important determinants of therapeutic response to DDR inhibitors. This review describes how both histone and DNA methylation affect DDR in the context of GC and discusses how alterations in DDR can help identify new molecular targets to devise more effective therapeutic strategies for GC, with a particular focus on HR-deficient tumors.

摘要翻译： 

胃癌作为全球最常见的恶性肿瘤之一，是一种由遗传和表观遗传改变累积发展而成的异质性疾病。在胃癌中，最为关键的表观遗传改变之一是DNA和组蛋白甲基化，这种修饰会影响细胞核内的多个过程，包括基因表达和DNA损伤修复。事实上，组蛋白甲基转移酶和去甲基化酶的异常表达会影响染色质对DNA修复机制的可及性；此外，DNA甲基转移酶的过度表达会导致启动子区域高甲基化，从而抑制参与DNA修复的基因转录。迄今为止，已发现多种DNA损伤修复机制，其中同源重组是修复双链断裂的主要途径。在胃癌中，越来越多的同源重组基因缺陷被发现，这有助于识别对DNA损伤修复抑制剂治疗反应的重要决定因素。本综述阐述了组蛋白和DNA甲基化如何影响胃癌中的DNA损伤修复，并讨论了DNA损伤修复的改变如何帮助识别新的分子靶点，从而为胃癌（特别是同源重组缺陷型肿瘤）制定更有效的治疗策略。

原文链接：

Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities