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Published on: October 27, 2014
Alternative Wnt-signaling axis leads to a break of oncogene-induced senescence
Viola Kluge1, Melanie Kappelmann-Fenzl1,2, Stefan Fischer2
1Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Abstract:
Oncogene-induced senescence (OIS) is an important process that suppresses tumor development, but the molecular mechanisms of OIS are still under investigation. It is known that BRAFV600E-mutated melanocytes can overcome OIS and develop melanoma, but the underlying mechanism is largely unknown. Using an established OIS model of primary melanocytes transduced with BRAFV600E, YAP activity was shown to be induced in OIS as well as in melanoma cells compared to that in normal epidermal melanocytes. This led to the assumption that YAP activation itself is not a factor involved in the disruption of OIS. However, its role and interaction partners potentially change. As Wnt molecules are known to be important in melanoma progression, these molecules were the focus of subsequent studies. Interestingly, activation of Wnt signaling using AMBMP resulted in a disruption of OIS in BRAFV600E-transduced melanocytes. Furthermore, depletion of Wnt6, Wnt10b or β-catenin expression in melanoma cells resulted in the induction of senescence. Given that melanoma cells do not exhibit canonical Wnt/β-catenin activity, alternative β-catenin signaling pathways may disrupt OIS. Here, we discovered that β-catenin is an interaction partner of YAP on DNA in melanoma cells. Furthermore, the β-catenin-YAP interaction changed the gene expression pattern from senescence-stabilizing genes to tumor-supportive genes. This switch is caused by transcriptional coactivation via the LEF1/TEAD interaction. The target genes with binding sites for LEF1 and TEAD are involved in rRNA processing and are associated with poor prognosis in melanoma patients. This study revealed that an alternative YAP-Wnt signaling axis is an essential molecular mechanism leading to OIS disruption in melanocytes.
Insights
Researchers discovered a new signaling pathway involving YAP and Wnt molecules that allows melanoma cells to bypass oncogene-induced senescence (OIS). This finding reveals a key mechanism driving melanoma development and offers potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Oncogene-induced senescence (OIS) is a crucial tumor suppressor mechanism.
- BRAFV600E mutation in melanocytes can lead to melanoma by overcoming OIS, but the underlying mechanisms remain unclear.
- YAP (Yes-associated protein) activity is induced in OIS and melanoma cells, suggesting its role may involve altered interactions rather than activation itself.
Purpose of the Study:
- To investigate the molecular mechanisms by which BRAFV600E-mutated melanocytes overcome OIS.
- To explore the role of YAP and Wnt signaling in melanoma progression and OIS evasion.
- To identify novel interaction partners and signaling pathways involved in melanoma development.
Main Methods:
- Utilized an established OIS model of primary melanocytes transduced with BRAFV600E.
- Investigated YAP activity and Wnt signaling activation (using AMBMP).
- Performed gene depletion studies for Wnt6, Wnt10b, and β-catenin in melanoma cells.
- Analyzed YAP-β-catenin interactions on DNA and downstream gene expression changes.
Main Results:
- YAP activity was induced in OIS and melanoma cells.
- Wnt signaling activation disrupted OIS in BRAFV600E-transduced melanocytes.
- Depletion of Wnt6, Wnt10b, or β-catenin induced senescence in melanoma cells.
- Discovered β-catenin as a DNA-binding interaction partner of YAP in melanoma cells.
- The β-catenin-YAP interaction shifted gene expression from senescence-stabilizing to tumor-supportive genes via LEF1/TEAD coactivation.
- Target genes involved in rRNA processing, regulated by LEF1/TEAD, correlate with poor melanoma prognosis.
Conclusions:
- An alternative YAP-Wnt signaling axis is essential for disrupting OIS in melanocytes.
- The interaction between YAP and β-catenin alters gene expression, promoting tumor progression.
- This pathway represents a novel molecular mechanism underlying melanoma development and suggests potential therapeutic targets.
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