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DHODH modulates transcriptional elongation in the neural crest and melanoma

Author

Listed:
  • Richard Mark White

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

  • Jennifer Cech

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

  • Sutheera Ratanasirintrawoot

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

  • Charles Y. Lin

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Peter B. Rahl

    (Whitehead Institute for Biomedical Research)

  • Christopher J. Burke

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

  • Erin Langdon

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

  • Matthew L. Tomlinson

    (School of Biological Sciences, University of East Anglia)

  • Jack Mosher

    (Center for Stem Cell Biology, University of Michigan, Howard Hughes Medical Institute)

  • Charles Kaufman

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

  • Frank Chen

    (Harvard University)

  • Hannah K. Long

    (Cambridge University)

  • Martin Kramer

    (Genzyme Corporation)

  • Sumon Datta

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

  • Donna Neuberg

    (Dana Farber Cancer Institute)

  • Scott Granter

    (Brigham and Women’s Hospital)

  • Richard A. Young

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Sean Morrison

    (Center for Stem Cell Biology, University of Michigan, Howard Hughes Medical Institute)

  • Grant N. Wheeler

    (School of Biological Sciences, University of East Anglia)

  • 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

  • Richard Mark White & Jennifer Cech & Sutheera Ratanasirintrawoot & Charles Y. Lin & Peter B. Rahl & Christopher J. Burke & Erin Langdon & Matthew L. Tomlinson & Jack Mosher & Charles Kaufman & Frank C, 2011. "DHODH modulates transcriptional elongation in the neural crest and melanoma," Nature, Nature, vol. 471(7339), pages 518-522, March.
    • Handle: RePEc:nat:nature:v:471:y:2011:i:7339:d:10.1038_nature09882
    DOI: 10.1038/nature09882
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    Cited by:

    1. Veronica Davalos & Claudia D. Lovell & Richard Itter & Igor Dolgalev & Praveen Agrawal & Gillian Baptiste & David J. Kahler & Elena Sokolova & Sebastian Moran & Laia Piqué & Eleazar Vega-Saenz de Mier, 2023. "An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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