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Effects of valproic acid on histone deacetylase inhibition in vitro and in glioblastoma patient samples.

ABSTRACT: AbstractBackgroundThe antiepileptic drug valproic acid (VPA) inhibits histone deacetylase in glioblastoma cells in vitro, which influences several oncogenic pathways and decreases glioma cell proliferation. The clinical relevance of these observations remains unclear, as VPA does not seem to affect glioblastoma patient survival. In this study, we analyzed whether the in vitro effects of VPA treatment on histone acetylation are also observed in tumor tissues of glioblastoma patients.MethodsThe in vitro effects of VPA treatment on histone acetylation were assessed with immunofluorescence and western blotting. On tissue microarrays and in fresh-frozen glioblastoma tissues we investigated the histone acetylation patterns of patients who were either treated with VPA or did not receive antiepileptic drugs at the time of their surgery. We also performed mRNA expression-based and gene set enrichment analyses on these tissues.ResultsVPA increased the expression levels of acetylated histones H3 and H4 in vitro, in agreement with previous reports. In tumor samples obtained from glioblastoma patients, however, VPA treatment affected neither gene (set) expression nor histone acetylation.ConclusionsThe in vitro effects of VPA on histone acetylation status in glioblastoma cells could not be confirmed in clinical tumor samples of glioblastoma patients using antiepileptic doses of VPA, which reflects the lack of effect of VPA on the clinical outcome of glioblastoma patients.

SUBMITTER: Berendsen S

PROVIDER: S-EPMC7212905 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Effects of the histone deacetylase inhibitor valproic acid on human pericytes in vitro.

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Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor.

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Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid.

Project description:The mechanisms of successful epigenetic reprogramming in cancer are not well characterized as they involve coordinated removal of repressive marks and deposition of activating marks by a large number of histone and DNA modification enzymes. Here, we have used a cross-species functional genomic approach to identify conserved genetic interactions to improve therapeutic effect of the histone deacetylase inhibitor (HDACi) valproic acid, which increases survival in more than 20% of patients with advanced acute myeloid leukemia (AML). Using a bidirectional synthetic lethality screen revealing genes that increased or decreased VPA sensitivity in C. elegans, we identified novel conserved sensitizers and synthetic lethal interactors of VPA. One sensitizer identified as a conserved determinant of therapeutic success of HDACi was UTX (KDM6A), which demonstrates a functional relationship between protein acetylation and lysine-specific methylation. The synthetic lethal screen identified resistance programs that compensated for the HDACi-induced global hyper-acetylation, and confirmed MAPKAPK2, HSP90AA1, HSP90AB1 and ACTB as conserved hubs in a resistance program for HDACi that are drugable in human AML cell lines. Hence, these resistance hubs represent promising novel targets for refinement of combinatorial epigenetic anti-cancer therapy.

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