PAX3 and ETS1 synergistically activate MET expression in melanoma cells

Melanoma is a highly aggressive disease that is difficult to treat due to rapid tumor growth, apoptotic resistance, and high metastatic potential. The MET tyrosine kinase receptor promotes many of these cellular processes, and while MET is often overexpressed in melanoma, the mechanism driving this overexpression is unknown. Since the MET gene is rarely mutated or amplified in melanoma, MET overexpression may be driven by 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. While 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, while the second site is PAX-independent. The induction of MET by ETS1 via this second site is enhanced by HGF-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.