TY - JOUR
T1 - Transcriptional attenuation in colon carcinoma cells in response to butyrate
AU - Daroqui, Maria C.
AU - Augenlicht, Leonard H.
PY - 2010/10
Y1 - 2010/10
N2 - The short-chain fatty acid sodium butyrate (NaB), produced in the colonic lumen, induces cell cycle arrest, differentiation, and/or apoptosis in colorectal carcinoma cells in vitro, establishing a potential role for NaB in colon cancer prevention. We have previously shown that butyrate decreases cyclin D1 and c-myc expression, each essential for intestinal tumor development, by transcriptional attenuation. Here, we determined that butyrate-induced transcriptional attenuation of the cyclin D1 and c-myc genes in SW837 human colorectal adenocarcinoma cells occurs at ∼100 nucleotides downstream of the transcription start site, with a similar positioning in Caco-2 cells. A concomitant decrease in RNA polymerase II occupancy at the 5′ end of each gene was observed. Because transcriptional regulation is associated with chromatin remodeling, we investigated by chromatin immunoprecipitation whether the histone deacetylase inhibitory activity of butyrate altered chromatin structure at the attenuated loci. Although the distributions of histone H3 trimethylated on K4 and K36 along the cyclin D1 and c-myc genes were consistent with current models, butyrate induced only modest decreases in these modifications, with a similar effect on acetylated H3 and a modest increase in histone H3 trimethylated on K27. Finally, transcriptome analysis using novel microarrays showed that butyrate-induced attenuation is widespread throughout the genome, likely independent of transcriptional initiation. We identified 42 loci potentially paused by butyrate and showed that the transcription patterns are gene specific. The biological functions of these loci encompass a number of effects of butyrate on the physiology of intestinal epithelial cells.
AB - The short-chain fatty acid sodium butyrate (NaB), produced in the colonic lumen, induces cell cycle arrest, differentiation, and/or apoptosis in colorectal carcinoma cells in vitro, establishing a potential role for NaB in colon cancer prevention. We have previously shown that butyrate decreases cyclin D1 and c-myc expression, each essential for intestinal tumor development, by transcriptional attenuation. Here, we determined that butyrate-induced transcriptional attenuation of the cyclin D1 and c-myc genes in SW837 human colorectal adenocarcinoma cells occurs at ∼100 nucleotides downstream of the transcription start site, with a similar positioning in Caco-2 cells. A concomitant decrease in RNA polymerase II occupancy at the 5′ end of each gene was observed. Because transcriptional regulation is associated with chromatin remodeling, we investigated by chromatin immunoprecipitation whether the histone deacetylase inhibitory activity of butyrate altered chromatin structure at the attenuated loci. Although the distributions of histone H3 trimethylated on K4 and K36 along the cyclin D1 and c-myc genes were consistent with current models, butyrate induced only modest decreases in these modifications, with a similar effect on acetylated H3 and a modest increase in histone H3 trimethylated on K27. Finally, transcriptome analysis using novel microarrays showed that butyrate-induced attenuation is widespread throughout the genome, likely independent of transcriptional initiation. We identified 42 loci potentially paused by butyrate and showed that the transcription patterns are gene specific. The biological functions of these loci encompass a number of effects of butyrate on the physiology of intestinal epithelial cells.
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U2 - 10.1158/1940-6207.CAPR-10-0083
DO - 10.1158/1940-6207.CAPR-10-0083
M3 - Article
C2 - 20841488
AN - SCOPUS:77958573090
SN - 1940-6207
VL - 3
SP - 1292
EP - 1302
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 10
ER -