Alternative Wnt-signaling axis leads to a break of oncogene-induced senescence

Kluge V, Kappelmann-Fenzl M, Fischer S, Zimmermann T, Pommer M, Kuphal S, Boßerhoff AK (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Cell Death & Disease Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group

Book Volume: 15

Article Number: 166

Journal Issue: 2

DOI: 10.1038/s41419-024-06550-8

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. (Figure presented.).

Authors with CRIS profile

Viola Kluge Lehrstuhl für Biochemie und Molekulare Medizin Melanie Kappelmann-Fenzl Lehrstuhl für Biochemie und Molekulare Medizin Tom Zimmermann Lehrstuhl für Biochemie und Molekulare Medizin Michaela Pommer Lehrstuhl für Biochemie und Molekulare Medizin Silke Kuphal Lehrstuhl für Biochemie und Molekulare Medizin Anja Katrin Boßerhoff Lehrstuhl für Biochemie und Molekulare Medizin

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

Related research project(s)

D031 (Biochemie u. Mol. Medizin: Modulation of oncogene-induced senescence by cell-matrix adhesion March 16, 2020 - March 15, 2023

Involved external institutions

Technische Hochschule Deggendorf DE Germany (DE)

How to cite

APA:

Kluge, V., Kappelmann-Fenzl, M., Fischer, S., Zimmermann, T., Pommer, M., Kuphal, S., & Boßerhoff, A.K. (2024). Alternative Wnt-signaling axis leads to a break of oncogene-induced senescence. Cell Death & Disease, 15(2). https://doi.org/10.1038/s41419-024-06550-8

MLA:

Kluge, Viola, et al. "Alternative Wnt-signaling axis leads to a break of oncogene-induced senescence." Cell Death & Disease 15.2 (2024).

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