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

  1. Kotaro Shirakawa
  2. Lan Wang
  3. Na Man
  4. Jasna Maksimoska
  5. Alexander W Sorum
  6. Hyung W Lim
  7. Intelly S Lee
  8. Tadahiro Shimazu
  9. John C Newman
  10. Sebastian Schröder
  11. Melanie Ott
  12. Ronen Marmorstein
  13. Jordan Meier
  14. Stephen Nimer
  15. Eric Verdin  Is a corresponding author
  1. Gladstone Institutes, United States
  2. University of Miami, United States
  3. University of Pennsylvania, United States
  4. National Cancer Institute, 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.

Article and author information

Author details

  1. Kotaro Shirakawa

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lan Wang

    University of Miami, Gables, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Na Man

    University of Miami, Gables, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jasna Maksimoska

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alexander W Sorum

    Chemical Biology Laboratory, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hyung W Lim

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Intelly S Lee

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Tadahiro Shimazu

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. John C Newman

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Sebastian Schröder

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Melanie Ott

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Ronen Marmorstein

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Jordan Meier

    Chemical Biology Laboratory, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Stephen Nimer

    University of Miami, Gables, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Eric Verdin

    Gladstone Institutes, San Francisco, United States
    For correspondence
    everdin@gladstone.ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Ali Shilatifard, Northwestern University Feinberg School of Medicine, United States

Publication history

  1. Received: August 26, 2015
  2. Accepted: May 26, 2016
  3. Accepted Manuscript published: May 31, 2016 (version 1)
  4. Accepted Manuscript updated: June 9, 2016 (version 2)
  5. Version of Record published: July 4, 2016 (version 3)

Copyright

© 2016, Shirakawa et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kotaro Shirakawa
  2. Lan Wang
  3. Na Man
  4. Jasna Maksimoska
  5. Alexander W Sorum
  6. Hyung W Lim
  7. Intelly S Lee
  8. Tadahiro Shimazu
  9. John C Newman
  10. Sebastian Schröder
  11. Melanie Ott
  12. Ronen Marmorstein
  13. Jordan Meier
  14. Stephen Nimer
  15. Eric Verdin
(2016)
Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity
eLife 5:e11156.
https://doi.org/10.7554/eLife.11156

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