PAX3 and ETS1 synergistically activate MET expression in melanoma cells

• 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
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.420

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.