title: Histone methylation-mediated silencing of miR-139 enhances invasion of non-small-cell lung cancer.
abstract: MicroRNA expression is frequently altered in human cancers, and some microRNAs act as oncogenes or tumor suppressors. MiR-139-5p (denoted thereafter as miR-139) has recently been reported to function as a tumor suppressor in several types of human cancer (hepatocellular carcinoma, colorectal cancer, breast cancer, and gastric cancer), but its function in non-small-cell lung cancer (NSCLC) and the mechanism of its suppression have not been studied in detail. MiR-139 was suppressed frequently in primary NSCLCs. MiR-139 is located within the intron of PDE2A and its expression was significantly correlated with the expression of PDE2A. A chromatin immunoprecipitation assay revealed that miR-139 was epigenetically silenced by histone H3 lysine 27 trimethylation (H3K27me3) of its host gene PDE2A and this process was independent of promoter DNA methylation. Pharmacological inhibition of both histone methylation and deacetylation-induced miR-139 with its host gene PDE2A. Ectopic expression of miR-139 in lung cancer cell lines did not affect the proliferation nor the migration but significantly suppressed the invasion through the extracellular matrix. In primary NSCLCs, decreased expression of miR-139 was significantly associated with distant lymph node metastasis and histological invasiveness (lymphatic invasion and vascular invasion) on both univariate and multivariate analyses. Collectively, these results suggest that H3K27me3-mediated silencing of miR-139 enhances an invasive and metastatic phenotype of NSCLC.
authors.affiliation: Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Amano
authors.affiliation: Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ishikawa
authors.affiliation: Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Sunohara
authors.affiliation: Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kage
authors.affiliation: Department of Cardiothoracic Surgery, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Ichinose
authors.affiliation: Department of Cardiothoracic Surgery, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sano
authors.affiliation: Department of Cardiothoracic Surgery, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakajima
authors.affiliation: Department of Pathology, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Department of Clinical Laboratory, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
authors.affiliation: Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.affiliation: Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ohishi
authors.affiliation: Department of Clinical Laboratory, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Daiya
authors.initials: D
authors.lastname: Takai
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D000066630:Ectopic Gene Expression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D011401:Promoter Regions, Genetic
chemical_list: D006657:Histones; C555098:MIRN139 microRNA, human; D035683:MicroRNAs; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human
keywords: Epigenetic repression; histones; lung neoplasms; microRNAs; neoplasm metastasis