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Overexpression of a fish CDKN2 gene in a hereditary melanoma model
S Kazianis1, L D Coletta, D C Morizot
1Department of Carcinogenesis, Science Park-Research Division, MD Anderson Cancer Center, University of Texas, PO Box 389, Smithville, TX 78957, USA. skazianis@sprd1.mdacc.tmc.edu
Abstract:
The fish genus Xiphophorus provides a vertebrate model useful in etiological studies of cancer. Hybrid fish can spontaneously develop melanomas deriving from the inheritance of melanistic pigment patterns and the simultaneous absence of proper genetic regulation. A cyclin-dependent kinase inhibitor gene, termed CDKN2X, was mapped to a genomic region that is implicated in fish melanoma tumor suppression. The related human tumor suppressor locus CDKN2A (P16, INK4A, MTS1) is deleted, mutated or transcriptionally repressed through methylation of cytosine bases within the 5' CpG island in a variety of neoplasms, including melanoma. The fish CDKN2X locus harbors a CpG island within its promoter and first exon, analogous in location to CpG islands in human CDKN2A and CDKN2B loci. The methylation state of individual CpG dinucleotides was investigated in genomic DNA derived from control tissues and melanomas within the CDKN2X 5' CpG island. The studied genomic area was found to be virtually unmethylated in all tested tissues including melanomas. In addition, RNA expression studies of the fish CDKN2X locus revealed that it is significantly overexpressed in melanoma, in contrast to what has been reported for the human CDKN2A locus in melanoma. Such overexpression may be a consequence of the pronounced upregulation of the Xmrk-2 receptor tyrosine kinase oncogene reported in several Xiphophorus melanoma models.
Insights
In Xiphophorus fish, the CDKN2X gene, a tumor suppressor, is not methylated in melanomas. Instead, this gene is overexpressed, unlike its human counterpart, in fish melanoma development.
Area of Science:
- Genetics
- Cancer Research
- Comparative Oncology
Background:
- The fish genus Xiphophorus serves as a vertebrate model for cancer etiology.
- Hybrid Xiphophorus fish develop melanomas due to inherited pigment patterns and lack of genetic regulation.
- The CDKN2X gene, a cyclin-dependent kinase inhibitor, is located in a melanoma tumor suppressor region in fish.
Purpose of the Study:
- To investigate the methylation status of the fish CDKN2X 5' CpG island in melanoma.
- To compare the expression of fish CDKN2X in melanoma with its human homolog, CDKN2A.
- To explore the role of CDKN2X in Xiphophorus melanoma development.
Main Methods:
- Investigated CpG dinucleotide methylation in the CDKN2X 5' CpG island using genomic DNA from control and melanoma tissues.
- Performed RNA expression studies to quantify CDKN2X locus expression in Xiphophorus melanomas.
Main Results:
- The 5' CpG island of the fish CDKN2X locus was found to be virtually unmethylated in all tested tissues, including melanomas.
- CDKN2X was significantly overexpressed in Xiphophorus melanoma tissues.
- This contrasts with the human CDKN2A locus, which is often repressed in human melanoma.
Conclusions:
- The tumor suppressor role of CDKN2X in Xiphophorus melanoma is not regulated by promoter methylation.
- Overexpression of CDKN2X in fish melanoma may be linked to the upregulation of the Xmrk-2 receptor tyrosine kinase oncogene.
- Findings highlight differences in melanoma pathogenesis between fish and human models.