Dietary Compound Resveratrol Is a Pan-BET Bromodomain Inhibitor
Dietary Compound Resveratrol Is a Pan-BET Bromodomain Inhibitor
复制标题
DOI：
10.3390/nu9111172
复制
发表时间：
2017-11-01
期刊：
影响因子：
5.9
通讯作者：
dos Santos, Jean Leandro
中科院分区：
文献类型：
--
作者：
Dutra, Luiz Antonio;Heidenreich, David;dos Santos, Jean Leandro
白藜芦醇（RSV）的化学预防和抗癌作用在文献中被广泛报道。具体而言，涉及表观遗传调节的机制是调节肿瘤发展的有希望的靶点。溴结构域通过识别组蛋白尾部的赖氨酸乙酰化并促进基因表达以调节组织特异性转录而充当表观遗传阅读器。在这项工作中，我们表明RSV是一种泛BET抑制剂。使用差示扫描荧光测定法（DSF），我们显示100 μ M的RSV使BET溴结构域的解链温度（Δ Tm）增加约2.0 ℃。使用等温滴定量热法（ITC）表征微摩尔解离常数（K-d）范围。在BRD 4的情况下，RSV K-d值为6.6 μ M（1）。分子对接提出RSV与BRD 4（1）的结合模式模拟乙酰基-赖氨酸相互作用。所有这些结果表明RSV也可以通过与BET布罗莫结构域相互作用来识别表观遗传阅读器结构域。
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 mu M increased the melting temperature (Delta Tm) of BET bromodomains by around 2.0 degrees C. The micromolar dissociation constant (K-d) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV K-d value accounted to 6.6 mu M in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.