title: Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity.
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.
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.|Department of Hematology and Oncology, Kyoto University, Kyoto, Japan.|Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: University of Miami, Gables, United States.|Sylvester Comprehensive Cancer Center, Miami, United States.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: University of Miami, Gables, United States.|Sylvester Comprehensive Cancer Center, Miami, United States.
authors.forename: Na
authors.initials: N
authors.lastname: Man
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Philadelphia, United States.
authors.forename: Jasna
authors.initials: J
authors.lastname: Maksimoska
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, Frederick, United States.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Sorum
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.
authors.forename: Hyung W
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.
authors.forename: Intelly S
authors.initials: IS
authors.lastname: Lee
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shimazu
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Newman
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schröder
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Philadelphia, United States.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, Frederick, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Meier
authors.affiliation: University of Miami, Gables, United States.|Sylvester Comprehensive Cancer Center, Miami, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Nimer
authors.affiliation: Gladstone Institutes, University of California, San Francisco, United States.|Department of Medicine, University of California, San Francisco, United States.
authors.forename: Eric
authors.identifier: 0000-0003-3703-3183
authors.initials: E
authors.lastname: Verdin
mesh_terms: D000105:Acetyl Coenzyme A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D004061:Diflunisal / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000075142:RUNX1 Translocation Partner 1 Protein / Q000235:genetics / Q000378:metabolism; D020156:Salicylic Acid / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000105:Acetyl Coenzyme A; D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004061:Diflunisal; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D020156:Salicylic Acid; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C107844:AML1-ETO fusion protein, human
keywords: acetylation; diflunisal; histone acetyltransferase; human biology; medicine; salicylate