DHODH modulates transcriptional elongation in the neural crest and melanoma

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 Chen, Hannah K. Long, Martin Kramer, Sumon Datta, Donna Neuberg, Scott Granter, Richard A. Young, Sean Morrison, Grant N. Wheeler and Leonard I. Zon ()
Additional contact information
Richard Mark White: Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School
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
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
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
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

Nature, 2011, vol. 471, issue 7339, 518-522

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/nature09882

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