Antagonistic Cross-Regulation between Sox9 and Sox10 Controls an Anti-tumorigenic Program in Melanoma

• Published in: PLoS genetics Vol. 11; no. 1; p. e1004877
• Main Authors: Shakhova, Olga, Cheng, Phil, Mishra, Pravin J., Zingg, Daniel, Schaefer, Simon M., Debbache, Julien, Häusel, Jessica, Matter, Claudia, Guo, Theresa, Davis, Sean, Meltzer, Paul, Mihic-Probst, Daniela, Moch, Holger, Wegner, Michael, Merlino, Glenn, Levesque, Mitchell P., Dummer, Reinhard, Santoro, Raffaella, Cinelli, Paolo, Sommer, Lukas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2015; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Carcinogenesis - genetics; Cell Line, Tumor; Colleges & universities; Experiments; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Hair Follicle; Health aspects; Homeostasis; Humans; Identification and classification; Medical research; Melanocytes - pathology; Melanoma; Melanoma - genetics; Melanoma - pathology; Mice; Proteins; RNA, Small Interfering; Rodents; Skin cancer; Smooth muscle; SOX9 Transcription Factor - biosynthesis; SOX9 Transcription Factor - genetics; SOXE Transcription Factors - biosynthesis; SOXE Transcription Factors - genetics; Stem cells; Transcription factors
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004877

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.