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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Defining Metabolic and Nonmetabolic Regulation of Histone Acetylation by NSAID Chemotypes
Molecular pharmaceutics, v 15(3), pp 729-736
01 Mar 2018
PMID: 29240439
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known for their effects on inflammatory gene expression. Although NSAIDs are known to impact multiple cellular signaling mechanisms, a recent finding is that the NSAID salicylate can disrupt histone acetylation, in part through direct inhibition of the lysine acetyltransferase (KAT) p300/CBP. While salicylate is a relatively weak KAT inhibitor, its CoA-linked metabolite is more potent; however, the ability of NSAID metabolites to inhibit KAT enzymes biochemically and in cells remains relatively unexplored. Here we define the role of metabolic and nonmetabolic mechanisms in inhibition of KAT activity by NSAID chemotypes. First, we screen a small panel of NSAIDs for biochemical inhibition of the prototypical KAT p300, leading to the finding that many carboxylate-containing NSAIDs, including ibuprofen, are able to function as weak inhibitors. Assessing the inhibition of p300 by ibuprofen-CoA, a known NSAID metabolite, reveals that linkage of ibuprofen to CoA increases its biochemical potency toward p300 and other KAT enzymes. In cellular studies, we find that carboxylate-containing NSAIDs inhibit histone acetylation. Finally, we exploit the stereoselective metabolism of ibuprofen to assess the role of its aryl-CoA metabolite in regulation of histone acetylation. This unique strategy reveals that formation of ibuprofen-CoA and histone acetylation are poorly correlated, suggesting metabolism may not be required for ibuprofen to inhibit histone acetylation. Overall, these studies provide new insights into the ability of NSAIDs to alter histone acetylation, and illustrate how selective metabolism may be leveraged as a tool to explore the influence of metabolic acyl-CoAs on cellular enzyme activity.
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Details
- Title
- Defining Metabolic and Nonmetabolic Regulation of Histone Acetylation by NSAID Chemotypes
- Creators
- Jonathan H. Shrimp - National Cancer InstituteJulie M. Garlick - National Cancer InstituteTugsan Tezil - Buck Institute for Research on AgingAlexander W. Sorum - NCI, Biol Chem Lab, Frederick, MD 21702 USAAndrew J. Worth - University of PennsylvaniaIan A. Blair - University of PennsylvaniaEric Verdin - Buck Institute for Research on AgingNathaniel W. Snyder - Drexel UniversityJordan L. Meier - National Cancer Institute
- Publication Details
- Molecular pharmaceutics, v 15(3), pp 729-736
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 8
- Grant note
- ZIABC011488 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U54HL11779 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA ZIA BC011488-04 / NIH, National Cancer Institute, Center for Cancer Research; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000427093600004
- Scopus ID
- 2-s2.0-85043253455
- Other Identifier
- 991019167954404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental
- Pharmacology & Pharmacy