title: Antagonistic cross-regulation between Sox9 and Sox10 controls an anti-tumorigenic program in melanoma.
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: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors: Olga
authors: O
authors: Shakhova
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Phil
authors: P
authors: Cheng
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Pravin J
authors: PJ
authors: Mishra
authors: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors: Daniel
authors: D
authors: Zingg
authors: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors: Simon M
authors: SM
authors: Schaefer
authors: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors: Julien
authors: J
authors: Debbache
authors: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors: Jessica
authors: J
authors: Häusel
authors: Department of Oncology, University Hospital Zurich, Schlieren, Switzerland.
authors: Claudia
authors: C
authors: Matter
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Theresa
authors: T
authors: Guo
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Sean
authors: S
authors: Davis
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Paul
authors: P
authors: Meltzer
authors: Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors: Daniela
authors: D
authors: Mihic-Probst
authors: Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors: Holger
authors: H
authors: Moch
authors: Institute of Biochemistry, Emil Fischer Center, FAU University of Erlangen-Nuernberg, Erlangen, Germany.
authors: Michael
authors: M
authors: Wegner
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Glenn
authors: G
authors: Merlino
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Mitchell P
authors: MP
authors: Levesque
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Reinhard
authors: R
authors: Dummer
authors: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.
authors: Raffaella
authors: R
authors: Santoro
authors: Division of Trauma Surgery, Center for Clinical Research, University Hospital Zurich, Zurich, Switzerland.
authors: Paolo
authors: P
authors: Cinelli
authors: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors: Lukas
authors: L
authors: Sommer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D018859:Hair Follicle; D006801:Humans; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D034741:RNA, Small Interfering; D055758:SOX9 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D055757:SOXE Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; C527923:SOX10 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055757:SOXE Transcription Factors
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