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Updated: Apr 19, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
PAX3 and ETS1 synergistically activate MET expression in melanoma cells
J D Kubic1, E C Little1, J W Lui1
1Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
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.
Insights
Transcription factors PAX3 and ETS1 synergistically activate MET expression in melanoma, driving tumor growth. Inhibiting these factors reduces MET levels and melanoma cell proliferation, revealing a new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Melanoma is an aggressive cancer characterized by rapid growth, resistance to apoptosis, and high metastatic potential.
- The MET proto-oncogene (MET) tyrosine kinase receptor is implicated in these processes and is often overexpressed in melanoma.
- The mechanism driving MET overexpression in melanoma is largely unknown, as MET gene mutations or amplifications are rare.
Purpose of the Study:
- To elucidate the mechanism of MET proto-oncogene (MET) overexpression in melanoma.
- To identify the transcription factors responsible for regulating MET expression in melanoma cells.
- To investigate the role of MET in melanoma progression and explore potential therapeutic strategies.
Main Methods:
- Analysis of the MET proto-oncogene (MET) 5' proximal promoter region.
- Investigation of transcription factor binding sites for PAX3 and ETS1.
- Experimental manipulation of PAX3 and ETS1 expression in melanoma cell lines.
- Assessment of MET receptor levels and melanoma cell growth in vitro and in vivo.
Main Results:
- Transcription factors PAX3 and ETS1 directly interact to synergistically activate MET expression.
- PAX3 and ETS1 bind to specific elements within the MET promoter, with PAX3-dependent and -independent activation sites identified.
- Inhibition of PAX3 and ETS1 significantly reduces MET receptor levels and impairs melanoma cell growth in vitro and in vivo.
- Hepatocyte growth factor enhances ETS1-mediated MET induction, indicating a positive feedback loop.
Conclusions:
- PAX3 and ETS1 play a critical role in driving MET proto-oncogene (MET) overexpression in melanoma through distinct promoter interactions.
- This PAX3/ETS1-MET pathway is crucial for melanoma cell proliferation and survival, representing a potential therapeutic target.
- Targeting PAX3 and ETS1 offers a promising strategy to inhibit melanoma progression by downregulating MET signaling.
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