文章：

组蛋白去乙酰化酶抑制剂和表观遗传（以及更多）癌症治疗的前景

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

原文发布日期：2006-01-01

DOI: 10.1038/nrc1779

类型: Review Article

开放获取: 否

要点：

1. Histone deacetylases (HDACs) and histone acetylases (HATs) are enzymes that are responsible for deacetylating and acetylating, respectively, the amino-terminal tails of histones. These chromatin changes regulate transcription and many other nuclear events.
2. Non-histone proteins (such as the oncosuppressor p53) and several cytoplasmic proteins are also regulated by HATs/HDACs.
3. Studies on the molecular pathogenesis of acute myeloid leukaemias have shown that the aberrant recruitment of HDACs has an important role in leukaemogenesis.
4. Leukaemia-associated fusion proteins (such as promyelocytic leukaemia (PML)–retinoic acid receptor (RAR) and acute myeloid leukaemia 1 (AML1)–ETO) recruit HDACs to repress the transcription of genes involved in differentiation (the fusion proteins therefore block differentiation) and impair the function of p53.
5. Alterations in the expression and/or activity of HATs/HDACs have been also observed in solid tumours. Solid tumours show decreased levels of histone acetylation, which correlates with clinical outcome.
6. HDAC inhibitors (HDACi) have been widely studied and belong to several chemical classes.
7. HDACi exert cell-type-specific effects inducing apoptosis, cell-cycle arrest, and differentiation.
8. In leukaemias, HDACi induce the expression of members of the tumour-necrosis factor-related apoptosis-inducing ligand (TRAIL) and FAS death receptor pathways. This induction is responsible for the pro-apoptotic effects of HDACi.
9. Clinical trials for several HDACi have started, and HDACi-responsive tumours have been observed.

要点翻译：

1. 组蛋白去乙酰化酶（HDACs）与组蛋白乙酰化酶（HATs）是分别负责对组蛋白氨基末端尾部进行去乙酰化和乙酰化修饰的酶类。这些染色质变化可调控转录及许多其他核内过程。
2. 非组蛋白（如抑癌蛋白p53）和若干胞质蛋白同样受HATs/HDACs的调控。
3. 对急性髓系白血病分子发病机制的研究表明，HDACs的异常募集在白血病发生中具有重要作用。
4. 白血病相关融合蛋白（如早幼粒细胞白血病-视黄酸受体融合蛋白PML-RAR和急性髓系白血病1-ETO融合蛋白AML1-ETO）通过募集HDACs来抑制分化相关基因的转录（这些融合蛋白因此阻断分化过程），并损害p53的功能。
5. 在实体肿瘤中也观察到HATs/HDACs表达水平和/或活性的改变。实体肿瘤显示组蛋白乙酰化水平降低，这与临床预后相关。
6. HDAC抑制剂（HDACi）已被广泛研究，涵盖多种化学类别。
7. HDACi能发挥细胞类型特异性效应，诱导细胞凋亡、细胞周期阻滞和分化。
8. 在白血病中，HDACi可诱导肿瘤坏死因子相关凋亡诱导配体（TRAIL）和FAS死亡受体通路成员的表达。这种诱导作用是HDACi促凋亡效应的关键机制。
9. 针对多种HDACi的临床试验已启动，并观察到HDACi应答性肿瘤的存在。

英文摘要：

Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.

摘要翻译： 

组蛋白去乙酰化酶（HDACs）被视为癌症治疗药物开发中最有前景的靶点之一，第一代组蛋白去乙酰化酶抑制剂（HDACi）目前正处于I/II期临床试验阶段。关于HDACs在肿瘤发生中的作用以及HDACi的作用机制，已有广泛深入的认识。然而，若干基础问题尚未完全阐明。结合当前对HDACi在体外和体内作用的理解，进一步探究这些基础问题，将有助于优化临床方案的设计。

原文链接：

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer