Fang Ming-Hao, Ji Xue-Mei
Department Emergency Internal Medicine, Tongji Hospital, Huazhong University of Sciences and Technology Tongji Medical College, Wuhan, Hubei Province, China.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Jun;17(3):816-20.
Histone modification is an important mechanism in oncogenesis and development of hematologic malignancies. Acetylation of lysine residues on histones and opening chromatin are correlated with activation of genes, whereas lysine residues methylation can result in either activation or repression on expressions of chromatin. The main point of all is deacetylation of histone mediated by histone deacetylases (HDACs). HDAC inhibitors are divided into 4 categories: short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides and benzamides, owning different mechanisms in HDAC inhibition. Many kinds of I/II phase clinical tests showed that all these HDAC inhibitors have obviously therapeutic efficacies in treatment of hematologic malignancies with low poisons. Combination of HDAC inhibitors with DNA demethylation drugs can decrease DNA methylation, increase histone acetylation and recover antioncogene expression. As important parts of epigenetics, histone acetylation and HDAC inhibitors possess positive prospects in treatment of hematologic malignancies. In this review the advances of study on mechanisms of histone modification, HDAC inhibitors and their use in treatment of hematologic malignancies are summarized.
组蛋白修饰是血液系统恶性肿瘤发生和发展的重要机制。组蛋白赖氨酸残基的乙酰化以及染色质的开放与基因激活相关，而赖氨酸残基的甲基化可导致染色质表达的激活或抑制。关键在于组蛋白去乙酰化酶（HDACs）介导的组蛋白去乙酰化。HDAC抑制剂分为4类：短链脂肪酸、异羟肟酸、环四肽和苯甲酰胺，它们在抑制HDAC方面具有不同的机制。多种I/II期临床试验表明，所有这些HDAC抑制剂在治疗血液系统恶性肿瘤方面均具有明显的治疗效果且毒性较低。HDAC抑制剂与DNA去甲基化药物联合使用可降低DNA甲基化，增加组蛋白乙酰化并恢复抑癌基因表达。作为表观遗传学的重要组成部分，组蛋白乙酰化和HDAC抑制剂在血液系统恶性肿瘤治疗中具有积极的前景。本文综述了组蛋白修饰机制、HDAC抑制剂及其在血液系统恶性肿瘤治疗中的应用研究进展。
