PAX3 and ETS1 synergistically activate MET expression in melanoma cells

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 m...

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Bibliographic Details
Published in:	Oncogene Vol. 34; no. 38; pp. 4964 - 4974
Main Authors:	Kubic, J D, Little, E C, Lui, J W, Iizuka, T, Lang, D
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 17-09-2015 Nature Publishing Group
Subjects:	13 13/1 13/106 38 42 42/41 631/67/1813/1634 82/51 Animals Apoptosis c-Met protein Cell Biology Cell culture Cell Line Cell Line, Tumor Cofactors Development and progression Ets-1 protein Genetic aspects Hepatocyte growth factor Hepatocyte Growth Factor - metabolism Human Genetics Humans Internal Medicine Kinases Medicine Medicine & Public Health Melanoma Melanoma - metabolism Melanoma - pathology MET protein Metastases Mice Oncogenes Oncology original-article Paired Box Transcription Factors - metabolism Pax3 protein PAX3 Transcription Factor Physiological aspects Promoter Regions, Genetic Protein expression Protein-tyrosine kinase receptors Proto-Oncogene Protein c-ets-1 - metabolism Proto-Oncogene Proteins c-met - genetics Proto-Oncogene Proteins c-met - metabolism Signal transduction Skin Neoplasms - metabolism Skin Neoplasms - pathology Transcription factors United States
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2014.420