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

Version 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.

Metrics

  • 4,611
    Page views
  • 1,188
    Downloads
  • 55
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.11156

Further reading

    1. Cancer Biology
    2. Computational and Systems Biology
    Bingrui Li, Fernanda G Kugeratski, Raghu Kalluri
    Research Article

    Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However, a rapid and flexible exosome-based diagnostic method to distinguish human cancers across cancer types in diverse biological fluids is yet to be defined. Here, we describe a novel machine learning-based computational method to distinguish cancers using a panel of proteins associated with exosomes. Employing datasets of exosome proteins from human cell lines, tissue, plasma, serum, and urine samples from a variety of cancers, we identify Clathrin Heavy Chain (CLTC), Ezrin, (EZR), Talin-1 (TLN1), Adenylyl cyclase-associated protein 1 (CAP1), and Moesin (MSN) as highly abundant universal biomarkers for exosomes and define three panels of pan-cancer exosome proteins that distinguish cancer exosomes from other exosomes and aid in classifying cancer subtypes employing random forest models. All the models using proteins from plasma, serum, or urine-derived exosomes yield AUROC scores higher than 0.91 and demonstrate superior performance compared to Support Vector Machine, K Nearest Neighbor Classifier and Gaussian Naive Bayes. This study provides a reliable protein biomarker signature associated with cancer exosomes with scalable machine learning capability for a sensitive and specific non-invasive method of cancer diagnosis.

    1. Cancer Biology
    Carolyn M Jablonowski, Waise Quarni ... Jun Yang
    Research Article

    Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that jumonji domain containing 6, arginine demethylase, and lysine hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven human neuroblastoma. JMJD6 cooperates with MYC in cellular transformation of murine neural crest cells by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a ‘molecular glue’ that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.