The short chain fatty acid butyrate induces promoter demethylation and reactivation of RARbeta2 in colon cancer cells.
It has been proposed that cancer prevention results from multiple dietary agents acting together as "action packages." Here we obtain evidence that butyrate, which is generated from dietary fiber, enhances the responsiveness of colon cancer cells to all-trans retinoic acid (ATRA). Evidence was obtained that this interaction depends on histone deactylase one (HDAC1) inhibition by butyrate and retinoic acid receptor alpha (RARalpha) activation by ATRA. The enhancement of RAR beta 2 (RARbeta2) activation was accompanied by a rapid demethylation of the RARbeta2 promoter. This demethylation could be achieved by butyrate alone, and it differed from that triggered by the DNA methyltransferase inhibitor 5-Aza-2' deoxycytidine in that it was 1) sporadic on the RARbeta2 promoter, 2) not genome wide, and 3) independent of extensive DNA replication. An analysis of inter-methylated sites assay indicated that only a few percent of loci analyzed showed reduced methylation. In colon cancer cells that were particularly resistant to RARbeta2 reactivation, the actions of butyrate could be further enhanced by the soy isoflavone genistein, which has also been reported to work through an epigenetic mechanism. These data suggest that dietary compounds that modulate epigenetic programming are likely to function best in the presence of retinoids and other cancer-preventing compounds that are sensitive to a cell's epigenetic state.
Spurling
Colleen C
CC
Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269-3125, USA.
Suhl
Joshua A
JA
Boucher
Nathalie
N
Nelson
Craig E
CE
Rosenberg
Daniel W
DW
Giardina
Charles
C
D015153:Blotting, Western / Q000379:methods; D002087:Butyrates / Q000494:pharmacology*; D018929:Cell Culture Techniques; D003110:Colonic Neoplasms / Q000235:genetics / Q000517:prevention & control*; D019175:DNA Methylation / Q000187:drug effects*; D006801:Humans; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D018168:Receptors, Retinoic Acid / Q000187:drug effects*
D002087:Butyrates; C533416:RARB2 protein, human; D018168:Receptors, Retinoic Acid