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Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP

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    Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP
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    • Beth E. Zucconi
      Beth E. Zucconi
      Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
      More by Beth E. Zucconi
    • Jessica L. Makofske
      Jessica L. Makofske
      Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
      Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, United States
      More by Jessica L. Makofske
    • David J. Meyers
      David J. Meyers
      Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
      More by David J. Meyers
    • Yousang Hwang
      Yousang Hwang
      Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
      More by Yousang Hwang
    • Mingxuan Wu
      Mingxuan Wu
      Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
      More by Mingxuan Wu
    • Mitzi I. Kuroda
      Mitzi I. Kuroda
      Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
      Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, United States
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    • Philip A. Cole*
      Philip A. Cole
      Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
      *E-mail: [email protected]
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      Orcidhttp://orcid.org/0000-0001-6873-7824
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    Biochemistry

    Cite this: Biochemistry 2019, 58, 16, 2133–2143
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.9b00160
    Published March 29, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain, which is inhibited by the small molecule A-485, and an acetyl-lysine binding bromodomain, which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.9b00160.

    • Biological replicates of A-485rs and I-CBP112 effects on prostate cancer cell proliferation, effects of BET bromodomain inhibitor OTX015 and triptolide in combination with A-485rs on prostate cancer cell proliferation, effects of A-485rs and I-CBP112 on mRNA levels of NF-κB and HIF1α in LNCaP cells, RNA-Seq replicates, and ChIP-PCR and qRT-PCR primers (PDF)

    Accession Codes

    EP300, Q09472; CBP, Q92793.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

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    This article is cited by 35 publications.

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    Biochemistry

    Cite this: Biochemistry 2019, 58, 16, 2133–2143
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.9b00160
    Published March 29, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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