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- Title
Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity.
- Authors
Kotaro Shirakawa; Lan Wang; Man, Na; Jasna Maksimoska; Sorum, Alexander W.; Lim, Hyung W.; Lee, Intelly S.; Tadahiro Shimazu; Newman, John C.; Schröder, Sebastian; Ott, Melanie; Marmorstein, Ronen; Meier, Jordan; Nimer, Stephen; Verdin, Eric
- 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.
- Subjects
SALICYLATES; DIFLUNISAL; ANTINEOPLASTIC agents; CYCLOOXYGENASE inhibitors; HISTONE acetylation; NF-kappa B; ASPIRIN; ACETYLCOENZYME A
- Publication
eLife, 2016, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.11156