Analysis of the Putative Tumor Suppressor Gene cdkn2ab in Pigment Cells and Melanoma of Xiphophorus and Medaka




Regneri, Janine
Klotz, Barbara
Wilde, Brigitta
Kottler, Verena A.
Hausmann, Michael
Kneitz, Susanne
Regensburger, Martina
Maurus, Katja
Gotz, Ralph
Lu, Yuan

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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.



cell cycle regulation, nevi, p16/INK4A, senescence, xmrk, Chemistry and Biochemistry


Regneri, 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.


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