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癌症的表观遗传疗法
Epigenetic Therapies for Cancer


Susan E. Bates ... 肿瘤 • 2020.08.13
相关阅读
• 表观遗传学在人类疾病预防与缓解中的关键作用

染色质是我们最早期发现的癌症治疗靶点之一。旨在改变染色质的药物开发可以追溯到20世纪70年代的分化剂及其与DNA甲基化的联系1。在癌症基因组测序揭示出许多染色质调节蛋白编码基因突变后,我们开始对染色质复杂性及其在肿瘤发生中的作用有了更精确了解。在许多情况下,这些突变被证明是维持恶变过程的关键,这一观察结果促使我们开发出了新的治疗方法。这篇综述总结了已批准的药物及其临床活性,介绍了正在开发的治疗方法,并描述了表观遗传学领域存在的挑战。

表观遗传学从DNA和组蛋白(染色质中在结构和功能上相互交织的两种大分子)开始。染色质的基本单位核小体是由重复的146 bp的DNA缠绕组蛋白八聚体构成。组蛋白家族包括H2A、H2B、H3、H4和多个变体,其中许多具有独特功能。DNA和组蛋白的修饰方式可调节DNA的可及性和功能,而这些修饰的改变是癌症的一个标志。表观遗传疗法试图使促进或维持恶性表型的组蛋白DNA甲基化模式和翻译后修饰恢复正常。

调节DNA胞嘧啶甲基化的酶及各种各样的翻译后组蛋白修饰可以调节DNA复制和修复以及RNA转录。富含赖氨酸的氨基末端组蛋白尾区的翻译后修饰包括乙酰化和甲基化,以及泛素化、磷酸化和sumo化。虽然存在多样性,但组蛋白修饰及其调节酶在被修饰组蛋白、受影响残基及在表观基因组中的作用方面具有显著的特异性——事实上,由于非常特异,产生了用于描述修饰的命名方法。例如,H3K9ac表示在组蛋白H3的第9位赖氨酸(K)残基上添加一个乙酰基(ac)。H3K9me3表示在同一氨基酸上添加3个甲基(me3)作为另一种修饰。乙酰化和甲基化通常被称为组蛋白标记,而不是翻译后修饰。乙酰化可导致开放、活跃的染色质状态,而甲基化较复杂,对染色质状态有不同效果,具体取决于修饰的残基。在一些位点(如H3K9),甲基化与染色质的抑制状态相关。而在另外一些位点(如H3K4),甲基化与基因转录相关。





作者信息

Susan E. Bates, M.D.
From the Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center and James J. Peters Veterans Affairs Medical Center, New York.

 

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