Valproic acid exposure decreases Cbp/p300 protein expression and histone acetyltransferase activity in P19 cells

Journal Article · Thu Sep 01 04:00:00 EDT 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2016.07.001· OSTI ID:22689253

Lamparter, Christina L. ^[1]

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1. Department of Biomedical and Molecular Sciences, Graduate Program in Pharmacology and Toxicology, Queen's University, Kingston, Ontario K7L 3N6 (Canada)

The teratogenicity of the antiepileptic drug valproic acid (VPA) is well established and its inhibition of histone deacetylases (HDAC) is proposed as an initiating factor. Recently, VPA-mediated HDAC inhibition was demonstrated to involve transcriptional downregulation of histone acetyltransferases (HATs), which was proposed to compensate for the increased acetylation resulting from HDAC inhibition. Cbp and p300 are HATs required for embryonic development and deficiencies in either are associated with congenital malformations and embryolethality. The objective of the present study was to characterize Cbp/p300 following VPA exposure in P19 cells. Consistent with previous studies, exposure to 5 mM VPA over 24 h induced a moderate decrease in Cbp/p300 mRNA, which preceded a strong decrease in total cellular protein mediated by ubiquitin-proteasome degradation. Nuclear Cbp/p300 protein was also decreased following VPA exposure, although to a lesser extent. Total cellular and nuclear p300 HAT activity was reduced proportionately to p300 protein levels, however while total cellular HAT activity also decreased, nuclear HAT activity was unaffected. Using the Cbp/p300 HAT inhibitor C646, we demonstrated that HAT inhibition similarly affected many of the same endpoints as VPA, including increased reactive oxygen species and caspase-3 cleavage, the latter of which could be attenuated by pre-treatment with the antioxidant catalase. C646 exposure also decreased NF-κB/p65 protein, which was not due to reduced mRNA and was not attenuated with catalase pre-treatment. This study provides support for an adaptive HAT response following VPA exposure and suggests that reduced Cbp/p300 HAT activity could contribute to VPA-mediated alterations. - Highlights: • VPA exposure in vitro downregulates Cbp/p300 mRNA and induces protein degradation. • Cbp/p300 histone acetyltransferase activity is similarly reduced with VPA exposure. • Inhibition of Cbp/p300 acetyltransferase activity induces apoptosis, involving ROS. • This inhibition of activity also reduces NFκB expression independently of ROS. • Reduced Cbp/p300 acetyltransferase activity may contribute to VPA teratogenesis.

• OSTI ID: 22689253
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 306; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETYLATION
ANTIOXIDANTS
APOPTOSIS
CATALASE
CONGENITAL DISEASES
CONGENITAL MALFORMATIONS
DRUGS
HISTONES
IN VITRO
INHIBITION
IODIDES
MESSENGER-RNA
ONTOGENESIS
OXYGEN
POLYETHYLENE GLYCOLS
POLYETHYLENES
TERATOGENESIS
TERATOGENS