title: FOXD3 modulates migration through direct transcriptional repression of TWIST1 in melanoma.
abstract: The neural crest is a multipotent, highly migratory cell population that gives rise to diverse cell types, including melanocytes. Factors regulating the development of the neural crest and emigration of its cells are likely to influence melanoma metastasis. The transcription factor FOXD3 plays an essential role in premigratory neural crest development and has been implicated in melanoma cell dormancy and response to therapeutics. FOXD3 is downregulated during the migration of the melanocyte lineage from the neural crest, and our previous work supports a role for FOXD3 in suppressing melanoma cell migration and invasion. Alternatively, TWIST1 is known to have promigratory and proinvasive roles in a number of cancers, including melanoma. Using ChIP-seq analysis, TWIST1 was identified as a potential transcriptional target of FOXD3. Mechanistically, FOXD3 directly binds to regions of the TWIST1 gene locus, leading to transcriptional repression of TWIST1 in human mutant BRAF melanoma cells. In addition, depletion of endogenous FOXD3 promotes upregulation of TWIST1 transcripts and protein. Finally, FOXD3 expression leads to a significant decrease in cell migration that can be efficiently reversed by the overexpression of TWIST1. These findings uncover the novel interplay between FOXD3 and TWIST1, which is likely to be important in the melanoma metastatic cascade.
  
  
  CONCLUSIONS
  FOXD3 and TWIST1 define distinct subgroups of cells within a heterogeneous tumor.
authors: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Michele B
authors: MB
authors: Weiss
authors: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Jefferson College of Graduate Studies, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Ethan V
authors: EV
authors: Abel
authors: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Neda
authors: N
authors: Dadpey
authors: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Andrew.Aplin@Jefferson.edu.
authors: Andrew E
authors: AE
authors: Aplin
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D009432:Neural Crest / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C503514:FOXD3 protein, human; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1