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Carcinogenesis Advance Access published online on September 28, 2006
Carcinogenesis, doi:10.1093/carcin/bgl167
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received March 29, 2006
Revised August 20, 2006
Accepted August 23, 2006

CANCER BIOLOGY

Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes

Snezana Milutinovic 1 {dagger}, Ana Catalina D'Alessio 1 {dagger}, Nancy Detich 1, and Moshe Szyf 1 *

1 Department of Pharmacology and Therapeutics, McGill University, Montreal Canada

* To whom correspondence should be addressed.
Moshe Szyf, E-mail: moshe.szyf{at}mcgill.ca


  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'-deoxycytidine (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 two of these genes, MELANOMA ANTIGEN B2 GENE (MAGEB2) and METALLOPROTEINASE 2 (MMP2), which are involved in tumor growth and metastasis. A chromatin immuno-precipitation (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 histone deacetylase 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.

Keywords: DNA methylation; demethylase; DNA demethylation; epigenetics; histone deacetylase inhibitors; MAGEB2; MMP2; 5-aza-2'-deoxycytidine; chromatin structure; histone acetylation.
{dagger}These authors contributed equally to the manuscript.
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