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Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR‐17‐92 cluster
Author(s) -
Humphreys Karen J.,
Cobiac Lynne,
Le Leu Richard K.,
Van der Hoek Mark B.,
Michael Michael Z.
Publication year - 2013
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.21879
Subject(s) - trichostatin a , microrna , biology , epigenetics , histone deacetylase , pten , histone deacetylase inhibitor , gene silencing , cancer research , vorinostat , cell growth , butyrate , sodium butyrate , apoptosis , histone , microbiology and biotechnology , gene , genetics , pi3k/akt/mtor pathway , biochemistry , fermentation
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.