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 Nimer, Eric Verdin

Research output: Contribution to journalArticle

33 Scopus citations

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

ASJC Scopus subject areas

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

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    Shirakawa, K., Wang, L., Man, N., Maksimoska, J., Sorum, A. W., Lim, H. W., Lee, I. S., Shimazu, T., Newman, J. C., Schröder, S., Ott, M., Marmorstein, R., Meier, J., Nimer, S., & 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