Carcinogenesis Advance Access originally published online on September 28, 2006
Carcinogenesis 2007 28(3):560-571; doi:10.1093/carcin/bgl167
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Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes
Department of Pharmacology and Therapeutics, McGill University Montreal, Canada
*To whom correspondence should be addressed at: 3655 Sir William Osler Promenade Rm 1309, Montreal, Quebec H3G 1Y6 Canada. Tel: 1 514 398 7107; Fax: 1 514 398 6690; Email: moshe.szyf{at}mcgill.ca
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.
Abbreviations: VPAvalproate, ; HDAC, histone deacetylase; 5-aza-CdR, 5-aza-2'-deoxy-cytidine; MAGEB2, melanoma antigen gene B2; MMP2, metalloproteinase 2, ChIP, chromatin immunoprecipitation; TSA, trichostatin A
These authors contributed equally to the work. Received March 29, 2006; revised August 20, 2006; accepted August 23, 2006.
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