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Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth

Author

Listed:
  • Jonathan B. Baell

    (Monash University
    Nanjing Tech University)

  • David J. Leaver

    (Monash University)

  • Stefan J. Hermans

    (St Vincent’s Institute of Medical Research)

  • Gemma L. Kelly

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Margs S. Brennan

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Natalie L. Downer

    (The Walter and Eliza Hall Institute of Medical Research, Parkville)

  • Nghi Nguyen

    (Monash University)

  • Johannes Wichmann

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Helen M. McRae

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Yuqing Yang

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Ben Cleary

    (Monash University)

  • H. Rachel Lagiakos

    (Monash University
    Cancer Therapeutics CRC)

  • Stephen Mieruszynski

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Guido Pacini

    (The Walter and Eliza Hall Institute of Medical Research, Parkville)

  • Hannah K. Vanyai

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Maria I. Bergamasco

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Rose E. May

    (The Walter and Eliza Hall Institute of Medical Research, Parkville)

  • Bethany K. Davey

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    Cancer Therapeutics CRC)

  • Kimberly J. Morgan

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Andrew J. Sealey

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Beinan Wang

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne
    Tsinghua University)

  • Natasha Zamudio

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Stephen Wilcox

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Alexandra L. Garnham

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Bilal N. Sheikh

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Brandon J. Aubrey

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Karen Doggett

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Matthew C. Chung

    (St Vincent’s Institute of Medical Research)

  • Melanie Silva

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    Cancer Therapeutics CRC)

  • John Bentley

    (Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program)

  • Pat Pilling

    (Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program)

  • Meghan Hattarki

    (Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program)

  • Olan Dolezal

    (Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program)

  • Matthew L. Dennis

    (Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program)

  • Hendrik Falk

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne
    Cancer Therapeutics CRC)

  • Bin Ren

    (Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program)

  • Susan A. Charman

    (Monash University)

  • Karen L. White

    (Monash University)

  • Jai Rautela

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Andrea Newbold

    (The Peter MacCallum Cancer Centre)

  • Edwin D. Hawkins

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Ricky W. Johnstone

    (The Peter MacCallum Cancer Centre)

  • Nicholas D. Huntington

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Thomas S. Peat

    (Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program)

  • Joan K. Heath

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Andreas Strasser

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Michael W. Parker

    (St Vincent’s Institute of Medical Research
    University of Melbourne)

  • Gordon K. Smyth

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Ian P. Street

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne
    Cancer Therapeutics CRC)

  • Brendon J. Monahan

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne
    Cancer Therapeutics CRC)

  • Anne K. Voss

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

  • Tim Thomas

    (The Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne)

Abstract

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5–KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4–6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

Suggested Citation

  • Jonathan B. Baell & David J. Leaver & Stefan J. Hermans & Gemma L. Kelly & Margs S. Brennan & Natalie L. Downer & Nghi Nguyen & Johannes Wichmann & Helen M. McRae & Yuqing Yang & Ben Cleary & H. Rache, 2018. "Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth," Nature, Nature, vol. 560(7717), pages 253-257, August.
    • Handle: RePEc:nat:nature:v:560:y:2018:i:7717:d:10.1038_s41586-018-0387-5
    DOI: 10.1038/s41586-018-0387-5
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    Citations

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    Cited by:

    1. Yosuke Komata & Akinori Kanai & Takahiro Maeda & Toshiya Inaba & Akihiko Yokoyama, 2023. "MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Dustin C. Becht & Brianna J. Klein & Akinori Kanai & Suk Min Jang & Khan L. Cox & Bing-Rui Zhou & Sabrina K. Phanor & Yi Zhang & Ruo-Wen Chen & Christopher C. Ebmeier & Catherine Lachance & Maxime Gal, 2023. "MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Jayme L. Dahlin & Bruce K. Hua & Beth E. Zucconi & Shawn D. Nelson & Shantanu Singh & Anne E. Carpenter & Jonathan H. Shrimp & Evelyne Lima-Fernandes & Mathias J. Wawer & Lawrence P. W. Chung & Ayushi, 2023. "Reference compounds for characterizing cellular injury in high-content cellular morphology assays," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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