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

Mol Carcinog. 2013 Jun;52(6):459-74. doi: 10.1002/mc.21879. Epub 2012 Feb 5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Apoptosis Regulatory Proteins / genetics
  • Bcl-2-Like Protein 11
  • Butyric Acid / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • HT29 Cells
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Membrane Proteins / genetics
  • MicroRNAs / genetics*
  • PTEN Phosphohydrolase / genetics
  • Phosphoproteins / genetics
  • Proto-Oncogene Proteins / genetics
  • RNA, Messenger / genetics
  • Transfection
  • Vorinostat

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • MIRN17 microRNA, human
  • MIRN17-92 microRNA, human
  • MIRN18A microRNA, human
  • MIRN19 microRNA, human
  • MIRN92 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • NEDD9 protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Butyric Acid
  • trichostatin A
  • Vorinostat
  • PTEN Phosphohydrolase
  • PTEN protein, human