1. Analysis of the putative tumor suppressor genecdkn2abin pigment cells and melanoma ofXiphophorusand medaka
- Author
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Susanne Kneitz, Verena A. Kottler, Janine Regneri, Barbara Klotz, Katja Maurus, Michael Hausmann, Yuan Lu, Ronald B. Walter, Amaury Herpin, Brigitta Wilde, Manfred Schartl, Martina Regensburger, Ralph Götz, Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, Department of Chemistry & Biochemistry - Molecular Biosciences Research Group, Texas State University, Laboratoire de Physiologie et Génomique des Poissons (LPGP), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Germany and Hagler Institute for Advanced Study and Department of Biology, Texas A&M University System, and This work was supported by the National Institutes of Health under award number R24OD018555, subaward number 215420C
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mélanome ,0301 basic medicine ,senescence ,Carcinogenesis ,[SDV]Life Sciences [q-bio] ,Melanoma, Experimental ,Oryzias ,markings ,Cyprinodontiformes ,Gene Knockout Techniques ,0302 clinical medicine ,poisson ,CDKN2A ,pigmentation ,Genes, Tumor Suppressor ,poeciliidae ,Phylogeny ,Melanoma ,Xiphophorus ,Phenotype ,homme ,Gene Expression Regulation, Neoplastic ,Oncology ,Multigene Family ,030220 oncology & carcinogenesis ,nevi ,Melanocytes ,cell cycle regulation ,régulation cellulaire ,expression des gènes ,tumor ,Tumor suppressor gene ,Transgene ,Dermatology ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Evolution, Molecular ,03 medical and health sciences ,tumeur ,man ,medicine ,cancer ,Animals ,human ,adrianichthyidae ,Epigenetics ,p16/INK4A ,neoplasms ,Gene ,Cyclin-Dependent Kinase Inhibitor p16 ,fish ,medaka ,medicine.disease ,biology.organism_classification ,Xiphphorus ,030104 developmental biology ,Cancer research ,humain ,xmrk - Abstract
In humans, the CDKN2A locus encodes two transcripts, INK4A and ARF. Inactivation of either one by mutations or epigenetic changes is a frequent signature of malignant melanoma and one of the most relevant entry points for melanomagenesis. To analyze whether cdkn2ab, the fish ortholog of CDKN2A, has a similar function as its human counterpart, we studied its action in fish models for human melanoma. Overexpression of cdkn2ab in a Xiphophorus melanoma cell line led to decreased proliferation and induction of a senescence‐like phenotype, indicating a melanoma‐suppressive function analogous to mammals. Coexpression of Xiphophorus cdkn2ab in medaka transgenic for the mitfa:xmrk melanoma‐inducing gene resulted in full suppression of melanoma development, whereas CRISPR/Cas9 knockout of cdkn2ab resulted in strongly enhanced tumor growth. In summary, this provides the first functional evidence that cdkn2ab acts as a potent tumor suppressor gene in fish melanoma models.
- Published
- 2018
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