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DHODH modulates transcriptional elongation in the neural crest and melanoma.

Abstract
Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.
AuthorsRichard 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, Leonard I Zon
JournalNature (Nature) Vol. 471 Issue 7339 Pg. 518-22 (Mar 24 2011) ISSN: 1476-4687 [Electronic] England
PMID21430780 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Isoxazoles
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • leflunomide
Topics
  • Amino Acid Substitution
  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation (drug effects)
  • Cell Line, Tumor
  • Cell Lineage (drug effects)
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Genes, p53 (genetics)
  • Humans
  • Isoxazoles (pharmacology, therapeutic use)
  • Melanoma (drug therapy, enzymology, genetics, pathology)
  • Mice
  • Neural Crest (drug effects, enzymology, metabolism, pathology)
  • Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, metabolism)
  • Proto-Oncogene Proteins B-raf (antagonists & inhibitors, chemistry, genetics, metabolism)
  • Rats
  • Stem Cells (cytology, drug effects, pathology)
  • Transcription, Genetic (drug effects, physiology)
  • Xenograft Model Antitumor Assays
  • Zebrafish (embryology, genetics)

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