title: MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms.
abstract: MicroRNA-224 (miR-224) is one of the most commonly up-regulated microRNAs in hepatocellular carcinoma (HCC), which affects crucial cellular processes such as apoptosis and cell proliferation. In this study, we aim to elucidate the molecular mechanism that leads to the overexpression of miR-224 in HCC. We examined the transcript expression of miR-224 and neighboring miR-452 and genes on chromosome Xq28 in tumor and paired adjacent nontumorous tissues from 100 patients with HCC and found that miR-224 is coordinately up-regulated with its neighboring microRNA (miRNA) and genes. This coordinated up-regulation of miRNAs and genes at the Xq28 locus can be mimicked in nontransformed immortalized human liver cells by the introduction of histone deacetylase (HDAC) inhibitors, which resulted in a corresponding increase in histone H3 acetylation in this region. This miR-224-residing locus in Xq28 is reciprocally regulated by HDAC1, HDAC3, and histone acetylase protein, E1A binding protein p300 (EP300). Notably, in HCC tumors that significantly overexpress microRNA-224, EP300 is also overexpressed and displays increased binding to the Xq28 locus. In transformed HCC cells, high miR-224 expression can be attenuated through the inhibition of EP300, using either siRNA or the specific drug C646. In summary, overexpression of EP300 may account, in part, for the up-regulation of miR-224 expression in patients with HCC.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.forename: Pierce
authors.initials: P
authors.lastname: Chow
authors.forename: Alexander Y F
authors.initials: AY
authors.lastname: Chung
authors.forename: David J
authors.initials: DJ
authors.lastname: Meyers
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: London L P J
authors.initials: LL
authors.lastname: Ooi
authors.forename: Caroline G L
authors.initials: CG
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D041321:Chromosomes, Human, X / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D056945:Hep G2 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation; D000099186:Histone Deacetylase 3
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D050881:E1A-Associated p300 Protein; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D006657:Histones; D035683:MicroRNAs; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D000099186:Histone Deacetylase 3; C546140:MIRN224 microRNA, human; C574051:MIRN452 microRNA, human; C494360:EP300 protein, human; C110550:HDAC1 protein, human