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Elife. 2016 May 31;5. pii: e11156. doi: 10.7554/eLife.11156.

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

Author information

1
Gladstone Institutes, University of California, San Francisco, United States.
2
Department of Medicine, University of California, San Francisco, United States.
3
Department of Hematology and Oncology, Kyoto University, Kyoto, Japan.
4
Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5
University of Miami, Gables, United States.
6
Sylvester Comprehensive Cancer Center, Miami, United States.
7
Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
8
Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Philadelphia, United States.
9
Chemical Biology Laboratory, National Cancer Institute, Frederick, United States.

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-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.

KEYWORDS:

acetylation; diflunisal; histone acetyltransferase; human biology; medicine; salicylate

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