Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

Abstract

Histone acetylation and deacetylation are crucial in the regulation of gene expression. Dynamic changes in gene expression may affect chromatin structure and, consequently, the interaction of chromatin with regulatory factors. In this study, the effects of the antiseizure drug valproic acid (VPA) on the expression of genes that regulate the structure of chromatin and the access of macromolecules to the DNA were investigated. Exposure of breast cancer cells to VPA resulted in rapid dose-dependent hyperacetylation of the histones H3 and H4. VPA further induced a depletion of several members of the structural maintenance of chromatin (SMC) proteins, SMC-associated proteins, DNA methyltransferase, and heterochromatin proteins. Down-regulation of these proteins was associated with chromatin decondensation. The observed alterations of chromatin structure correlated with enhanced sensitivity of DNA to nucleases and increased interaction of DNA with intercalating agents. VPA-induced chromatin decondensation led to a sequence-specific potentiation of DNA-damaging agents in cell culture and xenograft models. Modulation of heterochromatin maintenance proteins was not a direct, but a downstream, effect of histone acetylation. The effects on the chromatin structure were reversible upon drug withdrawal, but obligatory for the potentiation of DNA-damaging agents. In addition to their antitumor activity as single agents, the chromatin decondensation induced by histone deacetylase inhibitors may enhance the efficacy of cytotoxic agents that act by targeting DNA. The proposed mechanism of action suggests an effect of drug sequencing on the antitumor activity of these drugs. (Cancer Res 2005; 65(9): 3815-22)

Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells

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Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

“…The change in chromatin plasticity is associated with a depletion of chromatin remodelling proteins such as HP-1, structural maintenance of chromatin proteins (SMC1-5), and DNA methyltransferase 1 (Marchion et al, 2005b). Furthermore, depletion of topo IIa has been associated with chromatin decondensation (Adachi et al, 1991;Grue et al, 1998;Durrieu et al, 2000;Cuvier and Hirano, 2003;Marchion et al, 2005b).…”

Valproic Acid Affects Membrane Trafficking and Cell-Wall Integrity in Fission Yeast

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