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The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset

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  • Craig J. Ceol

    (Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School
    Present addresses: Program in Molecular Medicine, Program in Cell Dynamics, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. (C.J.C.); Departments of Surgery and Medicine, Weill Cornell Medical College and New York Presbyterian Hospital, New York, New York 10065, USA (Y.H.).)

  • Yariv Houvras

    (Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School
    Massachusetts General Hospital Cancer Center, Harvard Medical School
    Present addresses: Program in Molecular Medicine, Program in Cell Dynamics, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. (C.J.C.); Departments of Surgery and Medicine, Weill Cornell Medical College and New York Presbyterian Hospital, New York, New York 10065, USA (Y.H.).)

  • Judit Jane-Valbuena

    (Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
    The Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Steve Bilodeau

    (Whitehead Institute for Biomedical Research, 9 Cambridge Center)

  • David A. Orlando

    (Whitehead Institute for Biomedical Research, 9 Cambridge Center)

  • Valentine Battisti

    (UMR7216 Epigénétique et Destin Cellulaire, CNRS, Université Paris-Diderot, 35 rue Hélène Brion)

  • Lauriane Fritsch

    (UMR7216 Epigénétique et Destin Cellulaire, CNRS, Université Paris-Diderot, 35 rue Hélène Brion)

  • William M. Lin

    (Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
    The Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Travis J. Hollmann

    (Center for Molecular Oncologic Pathology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School)

  • Fabrizio Ferré

    (Sapienza University of Rome)

  • Caitlin Bourque

    (Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

  • Christopher J. Burke

    (Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

  • Laura Turner

    (Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

  • Audrey Uong

    (Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

  • Laura A. Johnson

    (Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
    The Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Rameen Beroukhim

    (Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
    The Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Craig H. Mermel

    (Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
    The Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Massimo Loda

    (Center for Molecular Oncologic Pathology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School)

  • Slimane Ait-Si-Ali

    (UMR7216 Epigénétique et Destin Cellulaire, CNRS, Université Paris-Diderot, 35 rue Hélène Brion)

  • Levi A. Garraway

    (Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
    The Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Richard A. Young

    (Whitehead Institute for Biomedical Research, 9 Cambridge Center)

  • Leonard I. Zon

    (Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

Abstract

Oncogenes BRAF(V600E) and SETDB1 in melanoma Transgenic zebrafish carrying the human oncogene BRAF(V600E), the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol et al. screen for genes that cooperate with mutated BRAF, and identify SETDB1 as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes SETDB1 as an important oncogene. White et al. find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors.

Suggested Citation

  • Craig J. Ceol & Yariv Houvras & Judit Jane-Valbuena & Steve Bilodeau & David A. Orlando & Valentine Battisti & Lauriane Fritsch & William M. Lin & Travis J. Hollmann & Fabrizio Ferré & Caitlin Bourque, 2011. "The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset," Nature, Nature, vol. 471(7339), pages 513-517, March.
    • Handle: RePEc:nat:nature:v:471:y:2011:i:7339:d:10.1038_nature09806
    DOI: 10.1038/nature09806
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    Cited by:

    1. Miranda V. Hunter & Reuben Moncada & Joshua M. Weiss & Itai Yanai & Richard M. White, 2021. "Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. David Lindgren & Gottfrid Sjödahl & Martin Lauss & Johan Staaf & Gunilla Chebil & Kristina Lövgren & Sigurdur Gudjonsson & Fredrik Liedberg & Oliver Patschan & Wiking Månsson & Mårten Fernö & Mattias , 2012. "Integrated Genomic and Gene Expression Profiling Identifies Two Major Genomic Circuits in Urothelial Carcinoma," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-11, June.
    3. Sumin Feng & Sai Ma & Kejiao Li & Shengxian Gao & Shaokai Ning & Jinfeng Shang & Ruiyuan Guo & Yingying Chen & Britny Blumenfeld & Itamar Simon & Qing Li & Rong Guo & Dongyi Xu, 2022. "RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Revati Darp & Marc A. Vittoria & Neil J. Ganem & Craig J. Ceol, 2022. "Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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