Valproate Induces widespread epigenetic reprogramming which involves demethylation of specific genes
Abstract
Valproate (VPA)(1) has been used for decades in the treatment of epilepsy, and is also effective as a mood stabilizer and in migraine therapy. It has been shown that VPA is also a histone deacetylase (HDAC) inhibitor. We have previously shown that VPA could trigger active demethylation of ectopically methylated transiently transfected DNA in HEK 293 cells. We therefore tested whether VPA treatment could bring about stable changes in the epigenome by causing changes in the state of DNA methylation of genomic DNA. Using a microarray gene expression analysis we identified the genes whose expression is induced by VPA treatment in HEK 293 cells. We found that a subset of these genes could also be induced by the classical DNA methylation inhibitor 5-aza-2'-deoxy-cytidine (5-aza-CdR) suggesting that VPA can alter the state of expression of genes, which are stably suppressed by DNA methylation. We mapped the state of methylation of three of these genes, MELANOMA ANTIGEN B2 GENE (MAGEB2), METALLOPROTEINASE 2 (MMP2) and WIF1, which are involved in tumor growth and metastasis. A chromatin immunoprecipitation (ChIP) assay revealed that VPA treatment caused as expected a change in the state of acetylation of these genes. Our data supports the concept that chromatin acetylation and DNA methylation are found in a dynamic interrelation and that the consequences of HDAC inhibitors are not limited to changes in histone acetylation but that they also bring about a change in the state of modification of DNA. The implications of our results on the future therapeutic utilities of VPA in cancer will be discussed.
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Milutinovic et al. (175) reported that valproate affects not only histone modification and gene expression, but also DNA de-methylation in human embryonic kidney cell lines, linking epigenetic modifications of both histones and DNA to gene expression.
“Milutinovic et al. (175) reported that valproate affects not only histone modification and gene expression, but also DNA de-methylation in human embryonic kidney cell lines, linking epigenetic modifications of both histones and DNA to gene expression.”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [175]
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- Authors
- Milutinovic, S., D'Alessio, A. C., Detich, N., & Szyf, M.
- Affiliations
- McGill University (CA)
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-03
- Volume
- 28
- Issue
- 3
- Pages
- 560-571
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- OpenAlex
- W2129768414
- Cited by
- 256
- References
- 54
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 4 · 2022: 19 · 2021: 9 · 2020: 10 · 2019: 11 · 2018: 9 · 2017: 16 · 2016: 16 · 2015: 11 · 2014: 14 · 2013: 11 · 2012: 27
- FWCI
- 5.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- valproic acid, histone deacetylase inhibitors, DNA methylation, epigenetic reprogramming, histone acetylation, gene expression, MMP-2, WIF1, decitabine, chromatin modification, tumor growth and metastasis, cancer therapy
- MeSH terms
- Antigens, Neoplasm, Cell Line, Chromatin, Histone Deacetylases, Humans, Kidney, Neoplasm Proteins, Repressor Proteins, Valproic Acid, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Matrix Metalloproteinase 2, Epigenesis, Genetic, Adaptor Proteins, Signal Transducing, Histone Deacetylase Inhibitors
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