Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity

Kotaro Shirakawa, Lan Wang, Na Man, Jasna Maksimoska, Alexander W. Sorum, Hyung W. Lim, Intelly S. Lee, Tadahiro Shimazu, John C. Newman, Sebastian Schröder, Melanie Ott, Ronen Marmorstein, Jordan Meier, Stephen D Nimer, Eric Verdin

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-kB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs.

Original languageEnglish (US)
Article numbere11156
JournaleLife
Volume5
Issue numberMAY2016
DOIs
StatePublished - May 31 2016

Fingerprint

Diflunisal
Salicylates
Metabolites
Lysine
Anti-Inflammatory Agents
Pharmaceutical Preparations
Plasma (human)
Acetylation
Acetyl Coenzyme A
AMP-Activated Protein Kinases
Acetyltransferases
NF-kappa B
Therapeutic Uses
Prostaglandin-Endoperoxide Synthases
Epigenomics
Histones
Aspirin
Oral Administration
Catalytic Domain
Leukemia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Shirakawa, K., Wang, L., Man, N., Maksimoska, J., Sorum, A. W., Lim, H. W., ... Verdin, E. (2016). Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. eLife, 5(MAY2016), [e11156]. https://doi.org/10.7554/eLife.11156

Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. / Shirakawa, Kotaro; Wang, Lan; Man, Na; Maksimoska, Jasna; Sorum, Alexander W.; Lim, Hyung W.; Lee, Intelly S.; Shimazu, Tadahiro; Newman, John C.; Schröder, Sebastian; Ott, Melanie; Marmorstein, Ronen; Meier, Jordan; Nimer, Stephen D; Verdin, Eric.

In: eLife, Vol. 5, No. MAY2016, e11156, 31.05.2016.

Research output: Contribution to journalArticle

Shirakawa, K, Wang, L, Man, N, Maksimoska, J, Sorum, AW, Lim, HW, Lee, IS, Shimazu, T, Newman, JC, Schröder, S, Ott, M, Marmorstein, R, Meier, J, Nimer, SD & Verdin, E 2016, 'Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity', eLife, vol. 5, no. MAY2016, e11156. https://doi.org/10.7554/eLife.11156
Shirakawa K, Wang L, Man N, Maksimoska J, Sorum AW, Lim HW et al. Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. eLife. 2016 May 31;5(MAY2016). e11156. https://doi.org/10.7554/eLife.11156
Shirakawa, Kotaro ; Wang, Lan ; Man, Na ; Maksimoska, Jasna ; Sorum, Alexander W. ; Lim, Hyung W. ; Lee, Intelly S. ; Shimazu, Tadahiro ; Newman, John C. ; Schröder, Sebastian ; Ott, Melanie ; Marmorstein, Ronen ; Meier, Jordan ; Nimer, Stephen D ; Verdin, Eric. / Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. In: eLife. 2016 ; Vol. 5, No. MAY2016.
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