Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors.
Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors.
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DOI：
10.1186/1868-7083-4-5
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发表时间：
2012-03-12
影响因子：
5.7
通讯作者：
Davie JR
中科院分区：
文献类型：
--
作者：
Delcuve GP;Khan DH;Davie JR
哺乳动物组蛋白去乙酰化酶（HDAC）家族由11种酶组成，它们在发育和组织稳态中具有特异性和关键性的功能。越来越多的证据表明，HDAC活性失调与许多肿瘤和非肿瘤疾病之间存在联系。因此，用于治疗的HDAC抑制剂的开发引起了学术研究人员和生物技术企业家的极大兴趣。许多HDAC抑制剂特异性和分子作用机制的研究正在进行中。在这些研究之一中，使用质谱来表征HDAC抑制剂对细胞提取物中的天然HDAC多蛋白复合物的亲和力和选择性。这种新的方法比使用纯化的蛋白质或蛋白质结构域作为靶点的标准研究更准确地再现体内分子相互作用，并且与目前测试或批准的抑制剂相比，这种新的方法在分离具有上级临床功效和降低的毒性的抑制剂方面非常有用。HDAC抑制剂诱导的转录重编程被认为在很大程度上有助于其治疗益处，其通过尚未完全理解的各种复杂机制来实现，包括组蛋白脱乙酰化、转录因子或调节因子（包括HDAC 1）脱乙酰化，随后是染色质重塑和关于转录起始的阳性或阴性结果。虽然只有很低比例的蛋白质编码基因受到HDAC抑制剂作用的影响，但约40%的非编码microRNA被上调或下调。此外，一个全新的长非编码RNA世界正在出现，揭示了一类新的HDAC抑制的潜在靶点。HDAC抑制剂也可能调节转录延伸，并已被证明会影响选择性剪接。
The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to a link between misregulated HDAC activity and many oncologic and nononcologic diseases. Thus the development of HDAC inhibitors for therapeutic treatment garners a lot of interest from academic researchers and biotechnology entrepreneurs. Numerous studies of HDAC inhibitor specificities and molecular mechanisms of action are ongoing. In one of these studies, mass spectrometry was used to characterize the affinities and selectivities of HDAC inhibitors toward native HDAC multiprotein complexes in cell extracts. Such a novel approach reproduces in vivo molecular interactions more accurately than standard studies using purified proteins or protein domains as targets and could be very useful in the isolation of inhibitors with superior clinical efficacy and decreased toxicity compared to the ones presently tested or approved. HDAC inhibitor induced-transcriptional reprogramming, believed to contribute largely to their therapeutic benefits, is achieved through various and complex mechanisms not fully understood, including histone deacetylation, transcription factor or regulator (including HDAC1) deacetylation followed by chromatin remodeling and positive or negative outcome regarding transcription initiation. Although only a very low percentage of protein-coding genes are affected by the action of HDAC inhibitors, about 40% of noncoding microRNAs are upregulated or downregulated. Moreover, a whole new world of long noncoding RNAs is emerging, revealing a new class of potential targets for HDAC inhibition. HDAC inhibitors might also regulate transcription elongation and have been shown to impinge on alternative splicing.
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