title: Histone deacetylase inhibitor induces cell apoptosis and cycle arrest in lung cancer cells via mitochondrial injury and p53 up-acetylation.
abstract: 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.
authors.affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Lianmin
authors.initials: L
authors.lastname: Bao
authors.affiliation: Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, 200032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Diao
authors.affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Dong
authors.affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Bingbin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Qiongya
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, 200032, China. yuheguo@163.com.
authors.forename: Heguo
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. xiangdong.wang@clintransmed.org.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. chenchengshui@126.com.
authors.forename: Chengshui
authors.initials: C
authors.lastname: Chen
mesh_terms: D000072283:A549 Cells; D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D063990:Gene Ontology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C541788:quisinostat
keywords: Acetylation; Apoptosis; Epithelial-mesenchymal transition; Histone deacetylase inhibitor; Mitochondria; p53