Activation of human cancer/testis antigen gene, XAGE‐1, in tumor cells is correlated with CpG island hypomethylation

Abstract

Expression of the XAGE-1 antigen is restricted to germ cells of the testis and a variety of neoplastic tissues. To date, the molecular mechanism for regulating expression of this cancer/testis antigen gene has been unknown. To evaluate methylation as a potential mechanism for regulating expression of this gene, we first correlated gene methylation status (measured by sequencing of bisulfide-modified DNA and COBRA) to expression of XAGE-1 mRNA in normal and cancerous cells. This analysis revealed dense methylation of the CpG island in the XAGE-1 gene promoter for the normal and cancerous cells that do not express this gene but loss of this methylation in normal testis, cancer cell lines and the primary gastric cancers where the gene is highly expressed. Further supporting the role of methylation in regulating expression of XAGE-1 were observations that treatment of 2 heavily methylated cell lines, SNU620 and HT29, with 5 0 -aza-deoxycytidine resulted in demethylation of XAGE-1 promoter and corresponding expression of this gene. Finally, we cloned various segments of the CpGrich XAGE-1 gene promoter linked to a luciferase reporter construct and transiently transfected this construct into HCT116 cells. These experiments confirmed transcriptional regulatory activity for the promoter region that incorporates the CpG island and demonstrated that in vitro methylation of this island results in loss of promoter activity. Collectively, these studies indicate that XAGE-1 expression in normal and cancerous tissues is regulated by methylation of the CpG island in the gene promoter. ' 2005 Wiley-Liss, Inc.

Loss of the SMRT/NCoR2 Corepressor Correlates with JAG2 Overexpression in Multiple Myeloma

“…CpG island methylation is a well-characterized epigenetic way in which gene transcription can be abnormally up-regulated or downregulated in nearly all types of cancer. Although CpG island hypermethylation is most commonly reported in cancer, some genes, such as the cancer-testis antigen genes, show hypomethylation at the CpG island contained in their promoters, which is associated with overexpression in cancer (26). We previously reported a potential involvement of DNA methylation of the CpG island spanning the JAG2 promoter region (12).…”

Concise Review: Cancer/Testis Antigens, Stem Cells, and Cancer

“…Some CTAs can be expressed in nongametogenic tissues such as the pancreas, liver, and spleen at levels far below that observed in germ cells [39]; 2) their expression programs are strictly regulated by epigenetic mechanisms such as DNA methylation [40]; and 3) they are immunogenic. To date, nearly 40 distinct CTAs have been identified based on immunogenic properties [41], expression profiles [42], and by bioinformatic methods [43].…”

Using epigenomic studies in monozygotic twins to improve our understanding of cancer

“…Even though only a minority of CGI promoters are methylated in normal somatic cells, there are a number of oncogenes identified that show a loss of methylation at their promoters and associated activation of gene expression in tumor tissues. These include key genes in tumorigenesis such as RRAS [55], MAGE1 [56], XAGE1A [57] and MASPIN [58]. Overall, the global loss of methylation is a key abnormality in cancer cells and is associated with repressive chromatin marks and silencing of genes within these regions.…”