| National Cancer Institute | Laboratory of Receptor Biology and Gene Expression | National Institutes of Health |
| Signal Transduction Group |
Regulation of the MMTV Promoter by Histone Deacetylase Inhibitors
Histone deacetylase (HDAC) inhibitors are an exciting new class of anticancer drugs. These compounds bind to and inhibit histone deacetylases and have the effect of increasing bulk levels of histone acetylation. These drugs are also known to promote differentiation or induce apoptosis in cultured tumor cells and several are now in clinical trials to assess their efficacy in treating various cancers.
MMTV is among a growing number of promoters known to be repressed by HDAC inhibitors. However, the mechanisms by which these drugs inhibit promoters are largely uncharacterized. First, it is often not known whether a gene responding to HDAC inhibitors is a primary or secondary target. Identification of primary target genes is essential to determining the mechanism by which these drugs directly modulate transcription. Second, the means by which certain genes are targeted specifically is unknown. Third, since increased histone acetylation is generally known to be conducive to transcription, how is repression achieved by these drugs?
The MMTV promoter is transcriptionally repressed by the HDAC inhibitor trichostatin A (TSA) in both the basal and glucocorticoid-activated states. This promoter is likely a direct target of the drug since its transcription is repressed immediately after treatment with TSA. The repression is complete within 30-60 minutes of drug administration.
Previous studies of MMTV repression by HDAC inhibitors suggested that the mechanism of repression was correlated with a loss in the ability of the glucocorticoid receptor (GR) to induce chromatin remodeling in the proximal promoter region. However, the duration of treatments were much longer than 1 hour. Our kinetic analysis of the inhibition of chromatin remodeling at the promoter shows that it occurs long after MMTV transcription is repressed. Thus the two effects of the drug are unlinked.
Current efforts are directed towards characterizing histone modifications at the MMTV promoter in the presence and absence of TSA. We are also interested in determining how the binding of transcription factors and coactivators changes in response to these drugs, and in determining which HDACs are involved in this process.
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