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