Abstract
Despite advances in the systemic treatment of patients with metastatic melanoma using immune checkpoint and tyrosine kinase inhibitors (TKI), the majority of stage IV melanoma patients eventually succumb to the disease. We have previously identified the transcription factor Sox10 as a crucial player in melanoma, yet the underlying molecular mechanisms mediating Sox10-dependent tumorigenesis remain largely uncharacterized. Here, we show that MEK and RAF inhibitors do not suppress levels of SOX10 protein in patient-derived cells in vitro, as well as in melanoma patients in vivo. In a search for pharmacological inhibitors of SOX10, we performed a mass spectrometry-based screen in human melanoma cells. Subsequent analysis revealed that SOX10 directly interacts with β-catenin, which is a key mediator of canonical Wnt/β-catenin signaling. We demonstrate that inhibitors of glycogen synthase kinase 3 alpha/beta (GSK3α/β) efficiently abrogate SOX10 protein in human melanoma cells in vitro and in melanoma mouse models in vivo. The mechanism of action of GSK3-mediated SOX10 suppression is transcription-independent and relies on the presence of a proteasome degradable form of β-catenin. Taken together, we provide evidence that activation of canonical Wnt signaling has a profound effect on melanoma growth and is able to counteract Sox10-dependent melanoma maintenance both in vitro and in vivo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4132-4154 |
| Number of pages | 23 |
| Journal | Oncogene |
| Volume | 39 |
| Issue number | 20 |
| DOIs | |
| State | Published - May 14 2020 |
Funding
Acknowledgements This work was supported by Oncosuisse, Pro-medica UBS Stiftung, Krebsliga Zurich, and Novartis Research Foundation to OS. We thank A. Serra-Roma, C-L Yang, O. Engeler for helpful suggestions and scientific discussions. We thank Dr Lor-enza Penengo (Institute of Molecular Cancer Research University of Zurich) for technical support and suggestions. We thank Dr Jelena Kühn-Georgijevic from Functional Genomic Center Zurich for her support in RNA sequencing. We thank Dr Daniel Zingg from Institute of Anatomy University of Zurich for kindly providing with Mel888 and Mel501 human melanoma cell lines. We thank Axel Zani and Redi Leraj for helping drawing the cartoons. We thank Cindy Lee for helpful discussion and critically reading of the manuscript. Finally, we would like to thank the University Research Priority Program (URPP) in translational cancer research biobank for the melanoma cell lines that were generated from surplus biopsy material from consenting patients at the University of Zurich Hospital (EK.647/800).
ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Cancer Research
