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

Histone deacetylase inhibition reveals competing roles for members of the oncogenic miR-17-92 cluster in colorectal cancer cells (#429)

Karen J Humphreys 1 , Lynne Cobiac 1 2 , Richard K Le Leu 1 2 , Mark B Van der Hoek 3 4 , Michael Z Michael 1
  1. Flinders Centre for Innovation in Cancer, Flinders University, Flinders Medical Centre, Adelaide, SA, Australia
  2. CSIRO Food and Nutritional Sciences, Adelaide, SA, Australia
  3. School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA, Australia
  4. Adelaide Microarray Centre, SA Pathology, Adelaide, SA, Australia

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 cultured 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). 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. The study also used chromatin immunoprecipitation to characterise the levels of acetylation and methylation at DNA-bound histone H3 at the locus of MIR17HG, the miR-17-92 host gene. In butyrate treated cells, decreased acetylation of H3K9, H3K14 and H3K27 and decreased tri-methylation of H3K4, centred around the transcription start site and proximal promoter of MIR17HG, suggests a direct epigenetic mechanism for decreased miR-17-92 cluster transcription in response to butyrate.