ArticleNature2011
DHODH modulates transcriptional elongation in the neural crest and melanoma.
Article in Nature, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 268 papers, 2 of them syntheses that pooled it.
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The trial behind it
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Who cites it
268 citing papers in PubMed, 2 syntheses or guidelines pooled it, 463 citations in OpenAlex.
- Drug repositioning: Progress and challenges in drug discovery for various diseases.European journal of medicinal chemistry · 2022Pooled it
- The Transcriptome of the Zebrafish Embryo After Chemical Exposure: A Meta-Analysis.Toxicological sciences : an official journal of the Society of Toxicology · 2017Pooled it
- Zebrafish against cancer: towards clinical relevance.Disease models & mechanisms · 2026Review
- Exploring the Role of the LCN2-DHODH Interaction in Mitochondrial Ferroptosis During Sepsis-Induced Myocardial Injury and LPS-Induced HL-1 Cardiomyocyte Injury.International journal of molecular sciences · 2026Article
- Pan-cancer characterization of the pyrimidine catabolic enzyme UPB1 identifies a tumor-suppressive prognostic biomarker in skin cutaneous melanoma.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Zebrafish swimming towards cures: a scalable NAM platform for drug discovery.Drug discovery today · 2026Review
- DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.Cell death & disease · 2026Article
- Radiogenomic landscape of the hallmarks of cancer.Biomarker research · 2026Review
- Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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- Multilevel Screening Platform Utilizing Cellular and Zebrafish Models to Identify Short Peptides with High Improvement of Motor Neuron Growth.International journal of molecular sciences · 2025Article
- CRATER tumor niches facilitate CD8Cell · 2025Article
- Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.Molecular biomedicine · 2025Article
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- Novel strategy to target glioblastoma-initiating cells using a braintropic adeno-associated virus carrying a miR-dependent genome-editing system.British journal of cancer · 2025Article
- Hypoxia-ischemia and sexual dimorphism: modeling mitochondrial dysfunction using brain organoids.Cell & bioscience · 2025Review
- DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.Nature communications · 2025Article
- Transcriptomic analysis of the anti-tumor effects of leflunomide in prolactinoma.Scientific reports · 2025Article
- Microbiota-indole-3-propionic acid-heart axis mediates the protection of leflunomide against αPD1-induced cardiotoxicity in mice.Nature communications · 2025Article
208 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
20 authors at 10 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.