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

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, Christopher J. Burke, Laura Turner, Audrey Uong, Laura A. Johnson, Rameen Beroukhim, Craig H. Mermel, Massimo Loda, Slimane Ait-Si-Ali, Levi A. Garraway, Richard A. Young and Leonard I. Zon ()
Additional contact information
Craig J. Ceol: Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School
Yariv Houvras: Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School
Judit Jane-Valbuena: Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
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
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
Rameen Beroukhim: Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
Craig H. Mermel: Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School
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
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

Nature, 2011, vol. 471, issue 7339, 513-517

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.

Date: 2011
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DOI: 10.1038/nature09806

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