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

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
The FASEB Journal (Impact Factor: 5.04). 03/2012; 26(7):3032-41. DOI: 10.1096/fj.11-201855
Source: PubMed


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.

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    • "Reportedly, cellular histone acetyltransferases, such as p300, and histone deacetylases, such as HDAC1, are regulated by HBx 59. A subsequent study found that p300 overexpression might be partially responsible for the upregulation of miR-224 expression observed in patients with HCC 60. Meanwhile, HBx can upregulate enhancer of zeste homolog 2 (EZH2), a histone lysine methyltransferase, which epigenetically silences several anti-metastasis miRNAs, including miR-139-5p, miR-125b, miR-101, and let-7c 61, 62. "
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    • "In other settings, histone acetylation is involved in the activation of oncomirs in cancer. For example, miR-224 is commonly upregulated in HCC, and there is reportedly a positive correlation between miR-224 expression and histone acetylase protein EP300 in HCC tumors (Wang et al., 2012). It is well documented that the breast cancer susceptibility gene BRCA1 is involved in DNA damage repair and cell cycle regulation, but a recent study revealed an interesting link between BRCA1 and the epigenetic regulation of oncomirs. "
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    ABSTRACT: MicroRNAs (miRNAs) play pivotal roles in numerous biological processes, and their dysregulation is a common feature of human cancer. Thanks to recent advances in the analysis of the cancer epigenome, we now know that epigenetic alterations, including aberrant DNA methylation and histone modifications, are major causes of miRNA dysregulation in cancer. Moreover, the list of miRNA genes silenced in association with CpG island hypermethylation is rapidly growing, and various oncogenic miRNAs are now known to be upregulated via DNA hypomethylation. Histone modifications also play important roles in the dysregulation of miRNAs, and histone deacetylation and gain of repressive histone marks are strongly associated with miRNA gene silencing. Conversely, miRNA dysregulation is causally related to epigenetic alterations in cancer. Thus aberrant methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Given that many of the silenced miRNAs appear to act as tumor suppressors through the targeting of oncogenes, re-expression of the miRNAs could be an effective approach to cancer therapy, and unraveling the relationship between epigenetic alteration and miRNA dysregulation may lead to the discovery of new therapeutic targets.
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    • "Actually, miR-224 overexpression can be attributed to histone acetylation rather than genomic amplification or DNA hypomethylation. The histone acetylase protein EP300 acts as a positive regulator in this regulation, whereas HDACs function as negative regulators [36]. Considering that miR-224 overexpression could not be totally attenuated by inhibition of histone acetylation, other factors might also contribute to miR-224 upregulation. "
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