Analysis of the putative tumor suppressor gene cdkn2ab in pigment cells and melanoma of Xiphophorus and medaka. (6th September 2018)

• Record Type: Journal Article
• Authors: Regneri, Janine; Klotz, Barbara; Wilde, Brigitta; Kottler, Verena A.; Hausmann, Michael; Kneitz, Susanne; Regensburger, Martina; Maurus, Katja; Götz, Ralph; Lu, Yuan; Walter, Ronald B.; Herpin, Amaury; Schartl, Manfred
• Is Part Of: Pigment cell & melanoma research. Volume 32:Number 2(2019)
• Page Start: 248
• Page End: 258
• Publication Date: 2018-09-06
• Subjects: cell cycle regulation -- nevi -- p16/INK4A -- senescence -- xmrk; Melanoma -- Periodicals; Chromatophores -- Periodicals; Animal pigments -- Periodicals; 616.99477
• DOI: 10.1111/pcmr.12729
• Languages: English
• ISSNs: 1755-1471

Abstract

Summary: 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.