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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
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
- Source :
- Oncogene. 24:4894-4907
- Publication Year :
- 2005
- Publisher :
- Springer Science and Business Media LLC, 2005.
-
Abstract
- Valproate (VPA) and trichostatin A (TSA), inhibitors of zinc-dependent deacetylase activity, induce reduction in the levels of mRNA encoding oestrogen receptor-alpha (ERalpha), resulting in subsequent clearance of ERalpha 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 ERalpha positive cells. Concomitant treatment with cycloheximide prevented most of these changes in gene expression, including downregulation of ERalpha 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 ERalpha expression. However, prolonged inhibition of the sirtuins by sirtinol also induces loss of ERalpha from cells. Mechanistically, we show that VPA invokes reversible promoter shutoff of the ERalpha, 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.
- Subjects :
- Genetic Markers
Cancer Research
medicine.medical_specialty
Transcription, Genetic
Breast Neoplasms
Biology
Hydroxamic Acids
Polymerase Chain Reaction
Cyclin D1
Cell Line, Tumor
Internal medicine
Genetics
medicine
Humans
Gene silencing
Gene Silencing
RNA, Messenger
RNA, Neoplasm
Enzyme Inhibitors
Promoter Regions, Genetic
Molecular Biology
DNA Primers
Regulation of gene expression
Base Sequence
Valproic Acid
Estrogen Receptor alpha
Cell cycle
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors
Kinetics
Tamoxifen
Trichostatin A
Endocrinology
DNA methylation
Sirtuin
Cancer research
biology.protein
Female
lipids (amino acids, peptides, and proteins)
Deacetylase activity
medicine.drug
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....f46cbe1e28e072956fae53718a41dd3c
- Full Text :
- https://doi.org/10.1038/sj.onc.1208662