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Analysis of the putative tumor suppressor gene cdkn2ab in pigment cells and melanoma of Xiphophorus and medaka.

Janine RegneriBarbara KlotzBrigitta WildeVerena A KottlerMichael HausmannSusanne KneitzMartina RegensburgerKatja MaurusRalph GötzYuan LuRonald B WalterAmaury HerpinManfred Schartl
Published in: Pigment cell & melanoma research (2018)
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.
Keyphrases
  • skin cancer
  • endothelial cells
  • crispr cas
  • dna methylation
  • induced apoptosis
  • basal cell carcinoma
  • signaling pathway
  • cell proliferation
  • dna damage
  • gene expression
  • genome editing
  • endoplasmic reticulum stress