Abstract
Abstract Cancer Testis Antigens (CTAs) are proteins that are normally expressed only in the male germ cells. These proteins are not expressed in other normal somatic tissues but are aberrantly upregulated in a variety of cancers like lung and melanoma. The expression of CTA genes is known to be regulated by promoter methylation. Using an integrative epigenetic screening approach, we have previously shown that CTAs are upregulated in non-small cell lung cancer and head and neck squamous cell carcinoma by promoter hypomethylation. Although it is now well accepted that CTAs are regulated by promoter methylation, the regulatory mechanisms of these genes remains unclear. Transcription factor BORIS (Brother Of the Regulator of Imprinted Sites) or CTCFL has been implicated in the regulation of two CTAs, mageA1 and NY-ESO-1. In the present study, we analyzed the expression of BORIS in a cohort of 16 melanoma tissues using quantitative reverse-transcription PCR. BORIS expression was detected in ∼70% of the tissues analyzed. Taking into account the evidence that BORIS regulates the expression of at least two CTAs, we also analyzed the expression of four CTAs, mageA1, mageA2, mageA3 and mageA4, in these tissues to assess the correlation between BORIS and CTA gene expression. We found that expression of mageA1, A2 and A3 correlated significantly with that of BORIS. We also analyzed two publicly available melanoma gene expression datasets and found that BORIS expression correlated with all four mageA genes analyzed. In our cohort as well as in the published gene expression datasets, the expression of the mageA genes tightly correlate with each other. Analysis of the methylation status of the mageA genes in our cohort showed that the methylation levels of mageA1, A2 and A3 genes also correlated with each other significantly. These observations support the phenomenon of coordinated CTA expression in solid tumors. We also found inverse correlation between the methylation and expression levels of these genes in some of the tissues analyzed. These results indicate that coordinated transcriptional regulation of the mageA genes may occur via promoter methylation dependent as well as independent mechanisms. Given the role of BORIS in the derepression of mageA1 gene via promoter demethylation, we also evaluated the correlation between BORIS expression and CTA promoter demethylation. We found that BORIS expression and mageA gene demethylation correlated in a subset of the tissues analyzed. The association between expression of BORIS and the mageA genes supports a role for BORIS as an effector in the upregulation of these genes. Also, the coordinated expression of the mageA genes suggests a common transcriptional mechanism for their regulation and our study presents evidence that implicates BORIS as a common regulator of the CTAs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5001. doi:10.1158/1538-7445.AM2011-5001
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