MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms

Yu Wang, Han Chong Toh, Pierce Chow, Alexander Y F Chung, David J Meyers, Philip A. Cole, London L P J Ooi, Caroline G L Lee

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3032-3041
Number of pages10
JournalFASEB Journal
Volume26
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

MicroRNAs
Epigenomics
Hepatocellular Carcinoma
Genes
Tumors
Up-Regulation
Histone Acetyltransferases
Acetylation
Histone Deacetylase Inhibitors
Cell proliferation
Chromosomes
Protein Binding
Liver
Histones
Small Interfering RNA
Neoplasms
Carrier Proteins
Display devices
Cell Proliferation
Tissue

Keywords

  • EP300
  • HDAC
  • Histone acetylation
  • miR-224

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Wang, Y., Toh, H. C., Chow, P., Chung, A. Y. F., Meyers, D. J., Cole, P. A., ... Lee, C. G. L. (2012). MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms. FASEB Journal, 26(7), 3032-3041. https://doi.org/10.1096/fj.11-201855

MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms. / Wang, Yu; Toh, Han Chong; Chow, Pierce; Chung, Alexander Y F; Meyers, David J; Cole, Philip A.; Ooi, London L P J; Lee, Caroline G L.

In: FASEB Journal, Vol. 26, No. 7, 07.2012, p. 3032-3041.

Research output: Contribution to journalArticle

Wang, Y, Toh, HC, Chow, P, Chung, AYF, Meyers, DJ, Cole, PA, Ooi, LLPJ & Lee, CGL 2012, 'MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms', FASEB Journal, vol. 26, no. 7, pp. 3032-3041. https://doi.org/10.1096/fj.11-201855
Wang, Yu ; Toh, Han Chong ; Chow, Pierce ; Chung, Alexander Y F ; Meyers, David J ; Cole, Philip A. ; Ooi, London L P J ; Lee, Caroline G L. / MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms. In: FASEB Journal. 2012 ; Vol. 26, No. 7. pp. 3032-3041.
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