title: SOX10 ablation arrests cell cycle, induces senescence, and suppresses melanomagenesis.
abstract: The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1(Tg)) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced expression of the melanocyte determining factor microphthalmia-associated transcription factor, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB, and reduced levels of its binding partner E2F1. As cell-cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma.
authors.affiliation: Authors' Affiliations: Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, Maryland; Maryland Melanoma Center at Medstar Franklin Square Medical Center, Baltimore, Maryland; Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland; Queensland Institute of Medical Research, Oncogenomics Laboratory, Brisbane, Australia; and Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Cronin
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Watkins-Chow
authors.forename: Art
authors.initials: A
authors.lastname: Incao
authors.forename: Joanne H
authors.initials: JH
authors.lastname: Hasskamp
authors.forename: Nicola
authors.initials: N
authors.lastname: Schönewolf
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Aoude
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Stacie K
authors.initials: SK
authors.lastname: Loftus
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence; D004195:Disease Models, Animal; D006801:Humans; D007124:Immunoenzyme Techniques; D008545:Melanoma / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055757:SOXE Transcription Factors / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D055757:SOXE Transcription Factors; C104077:metabotropic glutamate receptor type 1
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