Article

DHODH modulates transcriptional elongation in the neural crest and melanoma

Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 03/2011; 471(7339):518-22. DOI: 10.1038/nature09882
Source: PubMed

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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    • "Miller syndrome or postaxial acrofacial dysostosis (MIM 263750), characterised by both craniofacial and limb anomalies, is another example of a clinically recognisable acrofacial dysostosis in which recessive mutations in DHODH result in reduced de novo pyrimidine synthesis [Rainger et al., 2012]. Interestingly, inhibition of DHODH in zebrafish embryos leads to complete abrogation of neural crest development similar to Treacle [White et al., 2011]. The involvement of PHAX in PRS with or without CCA merits further work particularly in the absence of any human cases with intragenic mutations. "
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    • "White et al. [14] reported that leflunomide inhibits transcriptional elongation of the genes involved in self-renewal of neural progenitor cells through inhibition of DHO-DHase activity. These investigators further demonstrated that leflunomide at low doses cooperates with PLX4720, a B-Raf kinase inhibitor, to effectively inhibit melanoma cell proliferation and tumor growth [14]. Our early studies using a lymphadenopathy and autoimmune disease model in MRL/MpJ-lpr/lpr mice and a tumor xenograft model demonstrated that the immunosuppressive and antitumor activities of leflunomide are largely independent of the pyrimidine nucleotide synthesis pathway [4] [5] since uridine co-administration with leflunomide normalized pyrimidine nucleotide levels in tumor tissues but did not antagonize the antitumor activity of leflunomide in two xenograft models [5]. "
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    • "Dysregulation of neural-crest-specific genes is known to contribute to cancers in crest-derived tissues, such as melanocytes (tumors affecting melanocytes are termed melanoma). The group discovered that inhibitors of dihydroorotate dehydrogenase (DHODH) inhibit neural-crest development in larvae, and lead to a significant decrease in cancerous growths in the melanoma-prone zebrafish model (White et al., 2011). One such DHODH inhibitor used in the study, leflunomide, is an FDA-approved anti-arthritis drug. "
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