title: PAX3 and ETS1 synergistically activate MET expression in melanoma cells.
abstract: Melanoma is a highly aggressive disease that is difficult to treat owing to rapid tumor growth, apoptotic resistance and high metastatic potential. The MET proto-oncogene (MET) tyrosine kinase receptor promotes many of these cellular processes, but while MET is often overexpressed in melanoma, the mechanism driving this overexpression is unknown. As the MET gene is rarely mutated or amplified in melanoma, MET overexpression may be driven to increased activation through promoter elements. In this report, we find that transcription factors PAX3 and ETS1 directly interact to synergistically activate MET expression. Inhibition of PAX3 and ETS1 expression in melanoma cells leads to a significant reduction of MET receptor levels. The 300-bp 5' proximal MET promoter contains a PAX3 response element and two ETS1 consensus motifs. Although ETS1 can moderately activate both of these sites without cofactors, robust MET promoter activation of the first site is PAX dependent and requires the presence of PAX3, whereas the second site is PAX independent. The induction of MET by ETS1 via this second site is enhanced by hepatocyte growth factor-dependent ETS1 activation, thereby MET indirectly promotes its own expression. We further find that expression of a dominant-negative ETS1 reduces the ability of melanoma cells to grow both in culture and in vivo. Thus, we discover a pathway where ETS1 advances melanoma through the expression of MET via PAX-dependent and -independent mechanisms.
authors.affiliation: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Kubic
authors.affiliation: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Little
authors.affiliation: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Lui
authors.affiliation: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Iizuka
authors.affiliation: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lang
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C494041:ETS1 protein, human; C000715470:MAS1 protein, human; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met