title: HOXC11-SRC-1 regulation of S100beta in cutaneous melanoma: new targets for the kinase inhibitor dasatinib.
abstract: BACKGROUND
  Cutaneous melanoma is an aggressive disease. S100beta is an established biomarker of disease progression; however, the mechanism of its regulation in melanoma is undefined.
  
  
  METHODS
  Expression of HOXC11 and SRC-1 was examined by immunohistochemistry and immunofluorescence. Molecular and cellular techniques were used to investigate regulation of S100beta, including, western blot, qPCR, ChIP and migration assays.
  
  
  RESULTS
  Expression levels of the transcription factor HOXC11 and its coactivator SRC-1 were significantly elevated in malignant melanoma in comparison with benign nevi (P<0.001 and P=0.017, respectively, n=80), and expression of HOXC11 and SRC-1 in the malignant tissue associated with each other (P<0.001). HOXC11 recruitment to the promoter of S100beta was observed in the primary melanoma cell line SKMel28. S100beta expression was found to be dependant on both HOXC11 and SRC-1. Treatment with the Src/Abl inhibitor, dasatinib, reduced HOXC11-SRC-1 interaction and prevented recruitment of HOXC11 to the S100beta promoter. Dasatinib inhibited both mRNA and protein levels of S100beta and reduced migration of the metastatic cell line MeWo.
  
  
  CONCLUSIONS
  We have defined a signalling mechanism regulating S100beta in melanoma, which can be modulated by dasatinib. Profiling patients for expression of key markers of this network has the potential to increase the efficacy of dasatinib treatment.
authors.affiliation: Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, York House, York Street, Dublin 2, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: deBlacam
authors.forename: C
authors.initials: C
authors.lastname: Byrne
authors.forename: E
authors.initials: E
authors.lastname: Hughes
authors.forename: M
authors.initials: M
authors.lastname: McIlroy
authors.forename: F
authors.initials: F
authors.lastname: Bane
authors.forename: A D K
authors.initials: AD
authors.lastname: Hill
authors.forename: L S
authors.initials: LS
authors.lastname: Young
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D000069439:Dasatinib; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C484731:HOXC11 protein, human; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D013844:Thiazoles; D056920:Nuclear Receptor Coactivator 1; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib