Regneri, JanineKlotz, BarbaraWilde, BrigittaKottler, Verena A.Hausmann, MichaelKneitz, SusanneRegensburger, MartinaMaurus, KatjaGotz, RalphLu, YuanWalter, Ronald B.Herpin, AmaurySchartl, Manfred2020-03-162020-03-162019-03Regneri, J., Klotz, B., Wilde, B., Kottler, V. A., Hausmann, M., Kneitz, S., Regensburger, M., Maurus, K., Gotz, R., Lu, Y., Walter, R. B., Herpin, A., & Schartl, M. (2019). Analysis of the putative tumor suppressor gene cdkn2ab in pigment cells and melanoma of Xiphophorus and medaka. Pigment Cell and Melanoma Research, 32(2), pp. 248–258.1755-1471https://hdl.handle.net/10877/9454In 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.Text21 pages1 file (.pdf)encell cycle regulationnevip16/INK4AsenescencexmrkChemistry and BiochemistryArticlehttps://doi.org/10.1111/pcmr.12729