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BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer.

ABSTRACT: Aim of this study was to determine whether BORIS (Brother of the Regulator of Imprinted Sites) is a regulator of MAGEA2, MAGEA3, and MAGEA4 genes in lung cancer.Changes in expression of MAGEA genes upon BORIS induction/knockdown were studied. Recruitment of BORIS and changes in histone modifications at their promoters upon BORIS induction were analyzed. Luciferase assays were used to study their activation by BORIS. Changes in methylation at these promoters upon BORIS induction were evaluated.Alteration of BORIS expression by induction/knockdown directly correlated with expression of MAGEA genes. BORIS was enriched at their promoters in H1299 cells, which show high expression of these cancer testis antigens (CTA), compared with normal human bronchial epithelial (NHBE) cells which show low expression of the target CTAs. BORIS induction in A549 cells resulted in increased amounts of BORIS and activating histone modifications at their promoters along with a corresponding increase in their expression. Similarly, BORIS binding at these promoters in H1299 correlates with enrichment of activating modifications, whereas absence of BORIS binding in NHBE is associated with enrichment of repressive marks. BORIS induction of MAGEA3 was associated with promoter demethylation, but no methylation changes were noted with activation of MAGEA2 and MAGEA4.These data suggest that BORIS positively regulates these CTAs by binding and inducing a shift to a more open chromatin conformation with promoter demethylation for MAGEA3 or independent of promoter demethylation in case of MAGEA2 and MAGEA4 and may be a key effector involved in their derepression in lung cancer.

SUBMITTER: Bhan S

PROVIDER: S-EPMC3172963 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer.

Bhan Sheetal S Negi Sandeep S SS Shao Chunbo C Glazer Chad A CA Chuang Alice A Gaykalova Daria A DA Sun Wenyue W Sidransky David D Ha Patrick K PK Califano Joseph A JA

Clinical cancer research : an official journal of the American Association for Cancer Research 20110510 13

<h4>Purpose</h4>Aim of this study was to determine whether BORIS (Brother of the Regulator of Imprinted Sites) is a regulator of MAGEA2, MAGEA3, and MAGEA4 genes in lung cancer.<h4>Experimental design</h4>Changes in expression of MAGEA genes upon BORIS induction/knockdown were studied. Recruitment of BORIS and changes in histone modifications at their promoters upon BORIS induction were analyzed. Luciferase assays were used to study their activation by BORIS. Changes in methylation at these prom ...[more]

PMID: 21558405

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Project description:Myxoid and round-cell liposarcoma is a frequently encountered liposarcoma subtype. The mainstay of treatment remains surgical excision with or without chemoradiation. However, treatment options are limited in the setting of metastatic disease. Cancer-testis antigens are immunogenic antigens with the expression largely restricted to testicular germ cells and various malignancies, making them attractive targets for cancer immunotherapy. Gene expression studies have reported the expression of various cancer-testis antigens in liposarcoma, with mRNA expression of CTAG1B, CTAG2, MAGEA9, and PRAME described specifically in myxoid and round-cell liposarcoma. Herein, we further explore the expression of the cancer-testis antigens MAGEA1, ACRBP, PRAME, and SSX2 in myxoid and round-cell liposarcoma by immunohistochemistry in addition to determining mRNA levels of CTAG2 (LAGE-1), PRAME, and MAGEA3 by quantitative real-time PCR. Samples in formalin-fixed paraffin-embedded blocks (n=37) and frozen tissue (n=8) were obtained for immunohistochemistry and quantitative real-time PCR, respectively. Full sections were stained with antibodies to MAGEA1, ACRBP, PRAME, and SSX2 and staining was assessed for intensity (1-2+) and percent tumor positivity. The gene expression levels of CTAG2, PRAME, and MAGEA3 were measured by quantitative real-time PCR. In total, 37/37 (100%) of the samples showed predominantly strong, homogenous immunoreactivity for PRAME. There was a variable, focal expression of MAGEA1 (11%) and SSX2 (16%) and no expression of ACRBP. Quantitative real-time PCR demonstrated PRAME and CTAG2 transcripts in all eight samples: six tumors with high mRNA levels; two tumors with low mRNA levels. The gene expression of MAGEA3 was not detected in the majority of cases. In conclusion, myxoid and round-cell liposarcomas consistently express PRAME by immunohistochemistry as well as CTAG2 and PRAME by qualitative real-time PCR. This supports the use of cancer-testis antigen-targeted immunotherapy in the treatment of this malignancy.

Dataset Information

BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer.

Publications

BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer.

Similar Datasets

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