Abstract
BackgroundAs cancer-testis MAGE-A antigens are targets for tumor immunotherapy, it is important to study the regulation of their expression in cancers. This regulation appears to be rather complex and at the moment controversial. Although it is generally accepted that MAGE-A expression is controlled by epigenetics, the exact mechanisms of that control remain poorly understood.MethodsWe analyzed the interplay of another cancer-testis gene, BORIS, and the transcription factors Ets-1 and Sp1 in the regulation of MAGE-A1 gene expression performing luciferase assays, quantitative real-time PCR, sodium bisulfite sequencing, chromatin immunoprecipitation assays and pull down experiments.ResultsWe detected that ectopically expressed BORIS could activate and demethylate both endogenous and methylated reporter MAGE-A1 promoter in MCF-7 and micrometastatic BCM1 cancer cell lines. Overexpression of Ets-1 could not further upregulate the promoter activity mediated by BORIS. Surprisingly, in co-transfection experiments we observed that Sp1 partly repressed the BORIS-mediated stimulation, while addition of Ets-1 expression plasmid abrogated the Sp1 mediated repression of MAGE-A1 promoter. Both BORIS and Sp1 interacted with the TATA binding protein (hTBP) suggesting the possibility of a competitive mechanism of action between BORIS and Sp1.ConclusionsOur findings show that BORIS and Sp1 have opposite effects on the regulation of MAGE-A1 gene expression. This differential regulation may be explained by direct protein-protein interaction of both factors or by interaction of MAGE-A1 promoter with BORIS alternatively spliced isoforms with different sequence specificity. We also show here that ectopic expression of BORIS can activate transcription from its own locus, inducing all its splice variants.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-796) contains supplementary material, which is available to authorized users.
Highlights
As cancer-testis Melanoma-associated antigen A (MAGE-A) antigens are targets for tumor immunotherapy, it is important to study the regulation of their expression in cancers
Brother of the Regulator of Imprinted Sites (BORIS) stimulates MAGE-A1 mRNA expression in MCF-7 and BCM1 cells We previously demonstrated that the demethylating agent 5-aza-CdR and the histone deacetylase inhibitor Trichostatin A (TSA) synergistically upregulate MAGE-A1 expression in cell lines derived from different cancer types [6]
In order to examine whether BORIS is able to activate the MAGE-A1 promoter and to which extent, we compared its influence with the stimulatory effect of 5-aza-CdR and/or TSA on MAGE-A1 transcription in cancer cell line settings
Summary
As cancer-testis MAGE-A antigens are targets for tumor immunotherapy, it is important to study the regulation of their expression in cancers. It is generally accepted that MAGE-A expression is controlled by epigenetics, the exact mechanisms of that control remain poorly understood Based on their pronounced tumor specificity, cancer-testis antigens (CTA) which comprise numerous gene families, such as MAGE-A, are promising targets for specific anti-cancer immunotherapy. We observed that among the MBDs, the variant MBD1v1 of the five MBD1 isoforms has the ability to repress the unmethylated MAGE-A1 promoter and downregulate Ets-mediated transcriptional activation [11]. In line with our observation, a previous report demonstrated that the longer form of MBD2, the isoform MBD2a, is involved in gene repression and in promoting activation of the unmethylated cAMP-responsive genes by interaction with the RNA helicase A, and MBD2a may be either a transcriptional activator or repressor [13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
