title: PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma.
abstract: Metastatic melanoma is an aggressive and deadly disease. The chemokine receptor CXCR4 is active in melanoma metastasis, although the mechanism for the promotion and maintenance of CXCR4 expression in these cells is mostly unknown. Here, we find melanoma cells express two CXCR4 isoforms, the common version and a variant that is normally restricted to cells during development or to mature blood cells. CXCR4 expression is driven through a highly conserved intronic enhancer element by the transcription factors PAX3 and FOXD3. Inhibition of these transcription factors slows melanoma cell growth, migration, and motility, as well as reduces CXCR4 expression. Overexpression of these transcription factors drives the production of increased CXCR4 levels. Loss of PAX3 and FOXD3 transcription factor activity results in a reduction in cell motility, migration, and chemotaxis, all of which are rescued by CXCR4 overexpression. Here, we discover a molecular pathway wherein PAX3 and FOXD3 promote CXCR4 gene expression in melanoma.
authors.affiliation: From the Department of Medicine, Section of Dermatology and.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Kubic
authors.affiliation: From the Department of Medicine, Section of Dermatology and.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Lui
authors.affiliation: From the Department of Medicine, Section of Dermatology and.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Little
authors.affiliation: From the Department of Medicine, Section of Dermatology and.
authors.forename: Anton E
authors.initials: AE
authors.lastname: Ludvik
authors.affiliation: From the Department of Medicine, Section of Dermatology and.
authors.forename: Sasank
authors.initials: S
authors.lastname: Konda
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637 and.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: the Department of Cancer Biology and Kimmel Cancer Center, and Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
authors.affiliation: From the Department of Medicine, Section of Dermatology and dlang@medicine.bsd.uchicago.edu.
authors.forename: Deborah
authors.initials: D
authors.lastname: Lang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C527276:CXCR4 protein, human; C503514:FOXD3 protein, human; D051858:Forkhead Transcription Factors; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D019718:Receptors, CXCR4
keywords: DNA-protein interaction; gene expression; gene regulation; melanoma; transcription factor