title: 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.
authors: Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Richard Mark
authors: RM
authors: White
authors: Jennifer
authors: J
authors: Cech
authors: Sutheera
authors: S
authors: Ratanasirintrawoot
authors: Charles Y
authors: CY
authors: Lin
authors: Peter B
authors: PB
authors: Rahl
authors: Christopher J
authors: CJ
authors: Burke
authors: Erin
authors: E
authors: Langdon
authors: Matthew L
authors: ML
authors: Tomlinson
authors: Jack
authors: J
authors: Mosher
authors: Charles
authors: C
authors: Kaufman
authors: Frank
authors: F
authors: Chen
authors: Hannah K
authors: HK
authors: Long
authors: Martin
authors: M
authors: Kramer
authors: Sumon
authors: S
authors: Datta
authors: Donna
authors: D
authors: Neuberg
authors: Scott
authors: S
authors: Granter
authors: Richard A
authors: RA
authors: Young
authors: Sean
authors: S
authors: Morrison
authors: Grant N
authors: GN
authors: Wheeler
authors: Leonard I
authors: LI
authors: Zon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D000077339:Leflunomide; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009432:Neural Crest / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D007555:Isoxazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000077339:Leflunomide