Histone deacetylase inhibitor induces cell apoptosis and cycle arrest in lung cancer cells via mitochondrial injury and p53 up-acetylation.
Histone deacetylase inhibitor induces cell apoptosis and cycle arrest in lung cancer cells via mitochondrial injury and p53 up-acetylation.
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组蛋白脱乙酰酶抑制剂通过线粒体损伤和 p53 上乙酰化诱导肺癌细胞凋亡和周期停滞
DOI：
10.1007/s10565-016-9347-8
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发表时间：
2016-12
影响因子：
6.1
通讯作者：
Chen, Chengshui
中科院分区：
文献类型：
--
作者：
Bao, Lianmin;Diao, Hua;Dong, Nian;Su, Xiaoqiong;Wang, Bingbin;Mo, Qiongya;Yu, Heguo;Wang, Xiangdong;Chen, Chengshui
关键词：
非遗传毒性表型变化的可逆性已被探索，以开发新的预防和治疗癌症的方法。Quisinostat（JNJ-26481585）是一种新型的第二代组蛋白去乙酰化酶抑制剂（HDACi），对非小细胞肺癌（NSCLC）细胞具有有效的治疗作用。本研究旨在研究quisinostat对NSCLC细胞治疗活性的潜在分子机制。我们发现quisinostat以剂量和时间依赖性方式显著抑制A549细胞增殖。通过纳摩尔浓度的quisinostat处理诱导组蛋白H3和H4以及非组蛋白蛋白α-微管蛋白的乙酰化上调。我们还证明了quisinostat增加活性氧（ROS）的产生并破坏线粒体膜电位（Δ μ m），诱导细胞凋亡。此外，A549细胞暴露于quisinostat通过抑制上皮-间充质转化（EMT）过程显著抑制细胞迁移。生物信息学分析表明，quisinostat对NSCLC细胞的作用与激活p53信号通路有关。我们发现quisinostat增加了K382/K373位点的p53乙酰化，上调了p21（Waf 1/Cip 1）的表达，并导致G1期阻滞。因此，我们的研究结果表明，组蛋白去乙酰化酶可以作为NSCLC的治疗靶点，以发现和开发一种新的肺癌治疗方法。本文的在线版本（doi：10.1007/s10565-016-9347-8）包含补充材料，可供授权用户使用。
The reversibility of non-genotoxic phenotypic changes has been explored in order to develop novel preventive and therapeutic approaches for cancer. Quisinostat (JNJ-26481585), a novel second-generation histone deacetylase inhibitor (HDACi), has efficient therapeutic actions on non-small cell lung cancer (NSCLC) cell. The present study aims at investigating underlying molecular mechanisms involved in the therapeutic activity of quisinostat on NSCLC cells. We found that quisinostat significantly inhibited A549 cell proliferation in dose- and time-dependent manners. Up-acetylation of histones H3 and H4 and non-histone protein α-tubulin was induced by quisinostat treatment in a nanomolar concentration. We also demonstrated that quisinostat increased reactive oxygen species (ROS) production and destroyed mitochondrial membrane potential (ΔΨm), inducing mitochondria-mediated cell apoptosis. Furthermore, exposure of A549 cells to quisinostat significantly suppressed cell migration by inhibiting epithelial-mesenchymal transition (EMT) process. Bioinformatics analysis indicated that effects of quisinostat on NSCLC cells were associated with activated p53 signaling pathway. We found that quisinostat increased p53 acetylation at K382/K373 sites, upregulated the expression of p21(Waf1/Cip1), and resulted in G1 phase arrest. Thus, our results suggest that the histone deacetylase can be a therapeutic target of NSCLC to discover and develop a new category of therapy for lung cancer. The online version of this article (doi:10.1007/s10565-016-9347-8) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
3.3
作者：
Grant C;Rahman F;Piekarz R;Peer C;Frye R;Robey RW;Gardner ER;Figg WD;Bates SE
通讯作者：
Bates SE
影响因子：
13.5
作者：
Kaimori, Aki;Potter, James J.;Koteish, Ayman A.
通讯作者：
Koteish, Ayman A.
影响因子：
11.5
作者：
Arts, Janine;King, Peter;Angibaud, Patrick
通讯作者：
Angibaud, Patrick
DOI：
10.1073/pnas.51.5.786
发表时间：
1964-01-01
影响因子：
11.1
作者：
ALLFREY, VG;FAULKNER, R;MIRSKY, AE
通讯作者：
MIRSKY, AE