Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster

Karen Humphreys, Lynne Cobiac, Richard Le Leu, Mark Van der Hoek, Michael Michael

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    91 Citations (Scopus)


    Diet-derived butyrate, a histone deacetylase inhibitor (HDI), decreases proliferation and increases apoptosis in colorectal cancer (CRC) cells via epigenetic changes in gene expression. Other HDIs such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) have similar effects. This study examined the role of microRNAs (miRNAs) in mediating the chemo-protective effects of HDIs, and explored functions of the oncogenic miR-17-92 cluster. The dysregulated miRNA expression observed in HT29 and HCT116 CRC cells could be epigenetically altered by butyrate, SAHA and TSA. These HDIs decreased expression of miR-17-92 cluster miRNAs (P<0.05), with a corresponding increase in miR-17-92 target genes, including PTEN, BCL2L11, and CDKN1A (P<0.05). The decrease in miR-17-92 expression may be partly responsible for the anti-proliferative effects of HDIs, with introduction of miR-17-92 cluster miRNA mimics reversing this effect and decreasing levels of PTEN, BCL2L11, and CDKN1A (P<0.05). The growth effects of HDIs may be mediated by changes in miRNA activity, with down-regulation of the miR-17-92 cluster a plausible mechanism to explain some of the chemo-protective effects of HDIs. Of the miR-17-92 cluster miRNAs, miR-19a and miR-19b were primarily responsible for promoting proliferation, while miR-18a acted in opposition to other cluster members to decrease growth. NEDD9 and CDK19 were identified as novel miR-18a targets and were shown to be pro-proliferative genes, with RNA interference of their transcripts decreasing proliferation in CRC cells. This is the first study to identify competing roles for miR-17-92 cluster members, in the context of HDI-induced changes in CRC cells.

    Original languageEnglish
    Pages (from-to)459-474
    Number of pages16
    JournalMolecular Carcinogenesis
    Issue number6
    Early online date2013
    Publication statusPublished - Jun 2013


    • Butyrate
    • Colorectal cancer
    • Epigenetic
    • Histone deacetylase inhibitors
    • MicroRNAs
    • MiR-17-92


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