Antagonistic cross-regulation between Sox9 and Sox10 controls an anti-tumorigenic program in melanoma

Shakhova O, Cheng P, Mishra PJ, Zingg D, Schaefer SM, Debbache J, Haeusel J, Matter C, Guo T, Davis S, Meltzer P, Mihic-Probst D, Moch H, Wegner M, Merlino G, Levesque MP, Dummer R, Santoro R, Cinelli P, Sommer L (2015)

Publication Type: Journal article

Publication year: 2015

Journal

PLoS Genetics Public Library of Science

Publisher: Public Library of Science

Book Volume: 11

Pages Range: e1004877

Journal Issue: 1

DOI: 10.1371/journal.pgen.1004877

Abstract

Melanoma is the most fatal skin cancer, but the etiology of this devastating disease is still poorly understood. Recently, the transcription factor Sox10 has been shown to promote both melanoma initiation and progression. Reducing SOX10 expression levels in human melanoma cells and in a genetic melanoma mouse model, efficiently abolishes tumorigenesis by inducing cell cycle exit and apoptosis. Here, we show that this anti-tumorigenic effect functionally involves SOX9, a factor related to SOX10 and upregulated in melanoma cells upon loss of SOX10. Unlike SOX10, SOX9 is not required for normal melanocyte stem cell function, the formation of hyperplastic lesions, and melanoma initiation. To the contrary, SOX9 overexpression results in cell cycle arrest, apoptosis, and a gene expression profile shared by melanoma cells with reduced SOX10 expression. Moreover, SOX9 binds to the SOX10 promoter and induces downregulation of SOX10 expression, revealing a feedback loop reinforcing the SOX10 low/SOX9 high ant,m/ii-tumorigenic program. Finally, SOX9 is required in vitro and in vivo for the anti-tumorigenic effect achieved by reducing SOX10 expression. Thus, SOX10 and SOX9 are functionally antagonistic regulators of melanoma development.

Authors with CRIS profile

Michael Wegner Lehrstuhl für Biochemie und Pathobiochemie

Involved external institutions

University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Universitätsspital Zürich (USZ) CH Switzerland (CH) National Cancer Institute (NCI) US United States (USA) (US)

How to cite

APA:

Shakhova, O., Cheng, P., Mishra, P.J., Zingg, D., Schaefer, S.M., Debbache, J.,... Sommer, L. (2015). Antagonistic cross-regulation between Sox9 and Sox10 controls an anti-tumorigenic program in melanoma. PLoS Genetics, 11(1), e1004877. https://dx.doi.org/10.1371/journal.pgen.1004877

MLA:

Shakhova, Olga, et al. "Antagonistic cross-regulation between Sox9 and Sox10 controls an anti-tumorigenic program in melanoma." PLoS Genetics 11.1 (2015): e1004877.

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