Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability
Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability
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DOI：
10.1074/jbc.m113.490706
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发表时间：
2013-09-13
影响因子：
4.8
通讯作者：
Steiner, Pascal
中科院分区：
文献类型：
--
作者：
Lauffer, Benjamin E. L.;Mintzer, Robert;Steiner, Pascal
组蛋白去乙酰化酶（HDAC）在基因表达的控制中是关键的，并且其活性的失调已经涉及广泛的疾病，包括癌症、心血管和神经系统疾病。采用不同锌螯合功能（例如异羟肟酸和苯甲酰胺）的HDAC抑制剂（HDACi）在癌症治疗中显示出有希望的结果。尽管也有人提出，具有增加的同工酶选择性和效力的HDACi可以扩大其临床用途并使副作用最小化，但将这一想法转化为临床仍有待研究。此外，对具有不同药理学特性的HDACi如何影响体外和体内生物功能的详细了解仍然缺失。在这里，我们表明，一组含有苯甲酰胺的HDACi是缓慢的紧密结合抑制剂，具有较长的停留时间，不像含有异羟肟酸的HDACi伏立诺他和阿司他汀-A。在神经母细胞瘤细胞系SH-SY 5 Y中HDACi处理后H2 BK 5和H4 K14乙酰化的变化的表征揭示了组蛋白乙酰化的时间和幅度反映了抑制剂的缔合和解离动力学速率。相反，细胞活力和微阵列基因表达分析表明，细胞死亡诱导和转录调控的变化与HDACi的解离动力学速率无关。因此，我们的研究表明，确定HDACi的选择性和动力学抑制特性如何影响细胞功能将有助于评估其治疗效用。
Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation of their activity has been implicated in a broad range of diseases, including cancer, cardiovascular, and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. Although it has also been suggested that HDACi with increased isozyme selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here, we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi vorinostat and trichostatin-A. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histone acetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that determining how the selective and kinetic inhibition properties of HDACi affect cell function will help to evaluate their therapeutic utility.