Lakshmaiah K C, Jacob Linu A, Aparna S, Lokanatha D, Saldanha Smitha C
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.
J Cancer Res Ther. 2014 Jul-Sep;10(3):469-78. doi: 10.4103/0973-1482.137937.
Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling and histone covalent modifications. Post-translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and form the basis for "histone code". The enzymes Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) control the level of acetylation of histones and thereby alter gene expression. In many cancers, the balance between HAT and HDAC is altered. HDAC enzymes are grouped into four different classes namely Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Class III HDAC and Class IV (HDAC11). Histone Deacetylase Inhibitors (HDACI) exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates. The effects of HDACI on gene transcription are complex. They cause cell cycle arrest, inhibit DNA repair, induce apoptosis and acetylate non histone proteins causing downstream alterations in gene expression. HDACI are a diverse group of compounds, which vary in structure, biological activity, and specificity. In general, HDACIs contain a zinc-binding domain, a capping group, and a straight chain linker connecting the two. They are classified into four classes namely short chain fatty acids, hydroxamic acids, cyclic peptides and synthetic benzamides. This review describes the clinical utility of HDACI as monotherapy as well as combination therapy with other treatment modalities such as chemotherapy and radiotherapy. Adverse effects and shortcomings of treatment with HDACI are also discussed in detail.
表观遗传学是对基因表达中可遗传改变的研究，这些改变不伴有DNA序列的相应变化。三个相互关联的表观遗传过程在染色质水平调节基因表达，即DNA甲基化、核小体重塑和组蛋白共价修饰。发生在组蛋白尾部某些氨基酸残基上的翻译后修饰会改变染色质结构，并构成“组蛋白密码”的基础。组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）控制组蛋白的乙酰化水平，从而改变基因表达。在许多癌症中，HAT和HDAC之间的平衡发生了改变。HDAC酶分为四类，即I类（HDAC1、HDAC2、HDAC3和HDAC8）、II类（HDAC4、HDAC5、HDAC6、HDAC7、HDAC9和HDAC10）、III类HDAC和IV类（HDAC11）。组蛋白去乙酰化酶抑制剂（HDACI）通过促进组蛋白乙酰化以及促进非组蛋白蛋白质底物的乙酰化发挥抗癌活性。HDACI对基因转录的影响很复杂。它们导致细胞周期停滞，抑制DNA修复，诱导细胞凋亡，并使非组蛋白蛋白质乙酰化，从而引起基因表达的下游改变。HDACI是一类多样的化合物，其结构、生物活性和特异性各不相同。一般来说，HDACIs含有一个锌结合结构域、一个封端基团和连接两者的直链连接子。它们分为四类，即短链脂肪酸、异羟肟酸、环肽和合成苯甲酰胺。本综述描述了HDACI作为单一疗法以及与化疗和放疗等其他治疗方式联合治疗的临床应用。还详细讨论了HDACI治疗的不良反应和缺点。
