TY - JOUR TI - Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity AU - Shirakawa, Kotaro AU - Wang, Lan AU - Man, Na AU - Maksimoska, Jasna AU - Sorum, Alexander W AU - Lim, Hyung W AU - Lee, Intelly S AU - Shimazu, Tadahiro AU - Newman, John C AU - Schröder, Sebastian AU - Ott, Melanie AU - Marmorstein, Ronen AU - Meier, Jordan AU - Nimer, Stephen AU - Verdin, Eric A2 - Shilatifard, Ali VL - 5 PY - 2016 DA - 2016/05/31 SP - e11156 C1 - eLife 2016;5:e11156 DO - 10.7554/eLife.11156 UR - https://doi.org/10.7554/eLife.11156 AB - 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-κB 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. KW - salicylate KW - diflunisal KW - histone acetyltransferase KW - acetylation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -