title: miR-1236 regulates hypoxia-induced epithelial-mesenchymal transition and cell migration/invasion through repressing SENP1 and HDAC3.
abstract: Intratumoral hypoxia induces epithelial-mesenchymal transition and promotes cancer metastasis. MicroRNAs (miRNAs) are endogenous, single-strand RNA molecules that regulate gene expression. MiRNAs control cell growth, proliferation, differentiation and cell death and may function as oncogenes or tumor suppressors. HDAC3 and SENP1 are two molecules involved in hypoxia-induced EMT and HIF-1α stability, respectively. In this report, we show that miR-1236 plays a critical role in hypoxia-induced EMT and metastasis. MiRNA prediction programs TargetScan and miRanda show that miR-1236 may target HDAC3 and SENP1. MiR-1236 represses the luciferase activity of reporter constructs containing 3'UTR of HDAC3 and SENP1 as well as the expression levels of HDAC3 and SENP1. MiR-1236 abolishes hypoxia-induced EMT and inhibits migration and invasion activity of tumor cells. Hypoxia represses miR-1236 expression. The promoter region of miR-1236 is identified as the NELFE promoter. Twist1, an EMT regulator activated by hypoxia/HIF-1α, is shown to repress the reporter construct driven by the NELFE promoter. The binding site of Twist1 in the NELFE promoter is identified and chromatin immunoprecipitation assays show the direct binding of Twist1 to this site. Overexpression or knockdown of Twist1 in stable cell lines shows the inverse correlation between Twist1 and miR-1236 expression. These results identify a miRNA that regulates hypoxia-induced EMT and metastasis through repressing HDAC3 and SENP1 expression and present a regulatory network that involves many key players in hypoxia-induced EMT.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Sung-Yuan
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Teng
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: thcheng@ym.edu.tw.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Cheng
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan; Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan. Electronic address: wukj@mail.cmu.edu.tw.
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D002465:Cell Movement; D019295:Computational Biology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000072258:Tumor Hypoxia; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D020413:3' Untranslated Regions; D003546:Cysteine Endopeptidases; D006655:Histone Deacetylases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D009687:Nuclear Proteins; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000099186:Histone Deacetylase 3; C497442:HIF1A protein, human; C571208:MIRN1236 microRNA, human; C103173:TWIST1 protein, human; C118437:negative elongation factor; C404512:SENP1 protein, human
keywords: Epithelial–mesenchymal transition; HDAC3; SENP1; Twist1; miR-1236