Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

Abstract

Valproate (VPA) and trichostatin A (TSA), inhibitors of zinc-dependent deacetylase activity, induce reduction in the levels of mRNA encoding oestrogen receptor-a (ERa), resulting in subsequent clearance of ERa protein from breast and ovarian cell lines. Inhibition of oestrogen signalling may account for the endocrine disorders, menstrual abnormalities, osteoporosis and weight gain that occur in a proportion of women treated with VPA for epilepsy or for bipolar mood disorder. Transcriptome profiling revealed that VPA and TSA also modulate the expression of, among others, key regulatory components of the cell cycle. Meta-analysis of genes directly responsive to oestrogen indicates that VPA and TSA have a generally antioestrogenic profile in ERa positive cells. Concomitant treatment with cycloheximide prevented most of these changes in gene expression, including downregulation of ERa mRNA, indicating that a limited number of genes signal a hyperacetylated state within cells. Three members of the NAD-dependent deacetylases, the sirtuins, are upregulated by VPA and by TSA and sirtuin activity contributes to loss of ERa expression. However, prolonged inhibition of the sirtuins by sirtinol also induces loss of ERa from cells. Mechanistically, we show that VPA invokes reversible promoter shutoff of the ERa, pS2 and cyclin D1 promoters, by inducing recruitment of methyl cytosine binding protein 2 (MeCP2) with concomitant exclusion of the maintenance methylase DNMT1. Furthermore, we demonstrate that, in the presence of VPA, local DNA methylation, deacetylation and demethylation of activated histones and recruitment of inhibitory complexes occurs on the pS2 promoter.

Inhibition of tumor–stromal interaction through HGF/Met signaling by valproic acid

“…Nevertheless, the expression of some genes, including estrogen receptor α gene, the oncogene MYC and tumor suppressor gene p53, is down-regulated by histone acetylation induced by HDAC inhibitors [28]. Since VPA-and TSA-caused reduction in expression of most of those genes is blocked by concomitant treatment with cycloheximide, down-regulation of those genes by HDAC inhibitors is presumably dependent on the synthesis of transcriptional repressors [28]. Inhibition of up-regulated HGF gene expression by VPA, however, was not prevented by cycloheximide and was thus not such a case.…”

“…Since the down-regulation in most cases is prevented by concomitant treatment with cycloheximide, reduction of gene expression by HDAC inhibitors is presumably dependent on the synthesis of transcriptional repressors [28]. Thus, we tested whether VPA-caused repression of HGF gene up-regulation induced by PMA is such a case.…”

“…HDAC inhibitors generally activate expression of many genes, but the expression of some genes, including estrogen receptor α, is down-regulated by histone acetylation induced by HDAC inhibitors [28]. Since the down-regulation in most cases is prevented by concomitant treatment with cycloheximide, reduction of gene expression by HDAC inhibitors is presumably dependent on the synthesis of transcriptional repressors [28].…”

P4‐224: Epigenetic control of Aquaporin 1 expression by the amyloid precursor protein

“…Since inhibition of HDAC increases acetylation of histones leading to chromatin decondensation, TSA was expected to increase AQP1 mRNA. However, a TSA-mediated decrease in gene transcription has been observed for several genes (34,35) and could result from an increased expression of a transcription repressor. In that case, the effect of TSA can be reversed in the absence of protein synthesis (36).…”

Anti-estrogenic actions of histone deacetylase inhibitors in MCF-7 breast cancer cells

“…It is becoming clear that ER and HDACi pathways crosstalk at various levels such as expression and activity of ERa, regulation of p21 Waf1/Cip1 expression, cell proliferation, etc. (Reid et al 2005).…”