Curcumin-induced histone hypoacetylation: The role of reactive oxygen species
Curcumin-induced histone hypoacetylation: The role of reactive oxygen species
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DOI：
10.1016/j.bcp.2005.01.014
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发表时间：
2005-04-15
影响因子：
5.8
通讯作者：
Zhang, YT
中科院分区：
文献类型：
--
作者：
Kang, JH;Chen, J;Zhang, YT
姜黄素(Cur)是从姜黄中提取的一种著名的膳食色素，是一种很有前途的抗癌药物，但其体内靶分子尚不清楚。在此，我们报道了人肝癌细胞暴露于CURR后，组蛋白乙酰化水平显著降低。组蛋白乙酰转移酶(HAT)和组蛋白脱乙酰酶(HDAC)是体内控制组蛋白乙酰化状态的酶。在不加或不加组蛋白乙酰化抑制剂(HDAC特异性抑制剂)的情况下，Cur对组蛋白乙酰化有类似的抑制作用，但对HDAC的体外活性无影响。相反，p300(一种最有效的HAT蛋白)结构域的阴性可以阻断Cur对组蛋白乙酰化的抑制；Cur处理在体内和体外都显著抑制HAT活性。因此，是HAT而不是HDAC参与了CUR诱导组蛋白的低乙酰化。同时，细胞暴露于低或高浓度的Cur分别减少或增加了ROS的产生。抗氧化酶、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)或它们的组合可显著减轻Cur诱导的组蛋白乙酰化和HAT活性下降，但它们的热灭活形式不能显著减轻Cur诱导的组蛋白乙酰化和HAT活性下降。这些数据证明HAT是CUR的体内靶分子之一；通过抑制其活性，CUR在体内诱导组蛋白低乙酰化，其中ROS的产生起着重要作用。考虑到组蛋白乙酰化在真核基因转录中的关键作用，以及组蛋白低乙酰化参与高浓度Cur引起的细胞活力丧失，这些结果为我们进一步了解Cur体内功能的分子机制打开了新的大门。(C)2005 Elsevier Inc.保留所有权利。
Curcumin (Cur), a well-known dietary pigment derived from Curcuma longa, is a promising anticancer drug, but its in vivo target molecules remain to be clarified. Here we report that exposure of human hepatoma cells to Cur led to a significant decrease of histone acetylation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlling the state of histone acetylation in vivo. Cur treatment resulted in a comparable inhibition of histone acetylation in the absence or presence of trichostatin A (the specific HDAC inhibitor), and showed no effect on the in vitro activity of HDAC. In contrast, the domain negative of p300 (a most potent HAT protein) could block the inhibition of Cur on histone acetylation; and the Cur treatment significantly inhibited the HAT activity both in vivo and in vitro. Thus, it is HAT, but not HDAC that is involved in Cur-induced histone hypoacetylation. At the same time, exposure of cells to low or high concentrations of Cur diminished or enhanced the ROS generation, respectively. And the promotion of ROS was obviously involved in Cur-induced histone hypoacetylation, since Cur-caused histone acetylation and HAT activity decrease could be markedly diminished by the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) or their combination, but not by their heat-inactivated forms. The data presented here prove that HAT is one of the in vivo target molecules of Cur; through inhibiting its activity, Cur induces histone hypoacetylation in vivo, where the ROS generation plays an important role. Considering the critical roles of histone acetylation in eukaryotic gene transcription and the involvement of histone hypoacetylation in the lose of cell viability caused by high concentrations of Cur, these results open a new door for us to further understand the molecular mechanism involved in the in vivo function of Cur. (c) 2005 Elsevier Inc. All rights reserved.