Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster
Humphreys, KJ; Cobiac, L; Le Leu, RK; Van der Hoek, MB; Michael, MZ
HERO ID
1455022
Reference Type
Journal Article
Year
2012
Language
English
PMID
| HERO ID | 1455022 |
|---|---|
| In Press | No |
| Year | 2012 |
| Title | Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster |
| Authors | Humphreys, KJ; Cobiac, L; Le Leu, RK; Van der Hoek, MB; Michael, MZ |
| Journal | Molecular Carcinogenesis |
| Volume | 52 |
| Issue | 6 |
| Page Numbers | 459-474 |
| 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. © 2012 Wiley Periodicals, Inc. |
| Doi | 10.1002/mc.21879 |
| Pmid | 22308110 |
| Wosid | WOS:000317984500005 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | histone deacetylase inhibitors; butyrate; microRNAs; miR-17-92; colorectal cancer; epigenetic |