title: Histone deacetylases inhibitor trichostatin A increases the expression of Dleu2/miR-15a/16-1 via HDAC3 in non-small cell lung cancer.
abstract: Histone deacetylases (HDACs) inhibitor is a promising new approach to the treatment of lung cancer therapy via inhibiting cell growth and inducing apoptosis. miR-15a and miR-16-1 are important tumor suppressors through modulating B cell lymphoma 2 (Bcl-2), Cyclin D1, D2, and others. However, whether HDACs inhibitor modulates the expression of miR-15a/16-1 in lung cancer is still unknown. The purpose of our study was to identify a new miRNA-mediated mechanism which plays an important role in the anti-cancer effects of HDACs inhibitor. We found HDACs inhibitors trichostatin A (TSA) and sodium butyrate upregulated the expression of miR-15a/16-1, residing in the host tumor suppressor Dleu2 gene, through increasing the histone acetylation in the region of Dleu2/miR-15a/16-1 promoter in lung cancer cells. Moreover, among class Ι HDACs subtypes, only knockdown of HDAC3 by specific siRNA increased the hyperacetylation of Dleu2/miR-15a/16-1 promoter region and finally resulted in the upregulation of miR-15a/16-1. Furthermore, overexpression of miR-15a/16-1, which were always deleted or downregulated in lung cancer cells, effectively suppressed cell growth and reduced colony formation. Finally, TSA reduced the expression of Bcl-2, an important survival protein in lung cancer cells, partly through upregulation of miR-15a/16-1. Therefore, this offers a therapeutic strategy that lung cancer patients who exhibit low level of miR-15a/16-1 or high activity of HDACs may benefit from HDACs inhibitor-based therapy.
authors.affiliation: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical College, 2, FuXue Road, Wenzhou, 325000, China.
authors.forename: Chi-Qi
authors.initials: CQ
authors.lastname: Chen
authors.forename: Cheng-Shui
authors.initials: CS
authors.lastname: Chen
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Chen
authors.forename: Lian-Ping
authors.initials: LP
authors.lastname: Zhou
authors.forename: Hong-Lei
authors.initials: HL
authors.lastname: Xu
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Jin
authors.forename: Jian-Bo
authors.initials: JB
authors.lastname: Wu
authors.forename: Shen-Meng
authors.initials: SM
authors.lastname: Gao
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D020148:Butyric Acid / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D014166:Transferases; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000099186:Histone Deacetylase 3
chemical_list: D020148:Butyric Acid; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D062085:RNA, Long Noncoding; D014166:Transferases; D025521:Tumor Suppressor Proteins; D000099186:Histone Deacetylase 3; C109420:DLEU2 lncRNA, human; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; C012589:trichostatin A