期刊
CELL BIOLOGY AND TOXICOLOGY
卷 32, 期 6, 页码 469-482出版社
SPRINGER
DOI: 10.1007/s10565-016-9347-8
关键词
Acetylation; Apoptosis; Epithelial-mesenchymal transition; Mitochondria; p53; Histone deacetylase inhibitor
资金
- National Nature Science Foundation of China [31300959, 91230204, 81270099, 81320108001, 81270131, 81400035, 81570075, 81500058, 81500025]
- Science and Technology Commission of Shanghai Municipality [13ZR1435400]
- Shanghai Leading Academic Discipline Project [B115]
- Zhongshan Distinguished Professor Grant
- Shanghai Committee of Science and Technology [12JC1402200, 12431900207, 11410708600]
- Zhejiang Provincial Natural Science Foundation [Z15H010002]
- Zhejiang Provincial Science Technology Department Foundation [WKJ-ZJ-1526]
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 alpha-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 (Delta Im), 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.
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