Cancer testis antigens expression in mesothelioma: role of DNA methylation and bioimmunotherapeutic implications

Sigalotti, Luca; Coral, Sandra; Altomonte, Maresa; Natali, Lucia; Gaudino, Giovanni; Cacciotti, Paola; Libener, Roberta; Colizzi, Francesca; Vianale, Giovina; Martini, Fernanda; Tognon, Mauro; Jungbluth, Achim A.; Cebon, Jonathan; Maraskovsky, Eugene; Mutti, Luciano; Maio, Michele

doi:10.1038/sj.bjc.6600174

Cited by 83 publications

(70 citation statements)

References 18 publications

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“…In addition, Janssen et al (18) showed a strong 5-aza-CdR-induced MAGE-A1 expression, which did not correlate with the number of demethylated CpG sites in the Ets motif. Moreover, our findings are comparable with the results published by Sigalotti et al (27), who reported that the 5-aza-CdR-mediated overall DNA demethylation of CpG dinucleotides ranged from 6% to 12%. Similar to our data, Suyama et al (21) failed to detect a clear relation between DNA demethylation of CpG dinucleotides in both Ets sites of the MAGE-A1 promoter and its transcriptional expression in different 5-aza-CdR-stimulated cell lines.…”

Section: Discussionsupporting

confidence: 83%

“…Whereas reverse transcription-PCR analysis showed a small effect of trichostatin A on transcription, transfection studies showed that trichostatin A was able to significantly up-regulate promoter-driven luciferase activity of the methylated and even unmethylated reporter plasmids containing each of the four promoter fragments with the exception of the methylated MAGE-A3 construct. In agreement with previous studies (25,27), DNA methylation of transfected reporter constructs could strongly down-regulate promoter activity, which correlated to the methylation-dependent regulation of these genes. Whereas the methylation of the rare HpaII CCGG motifs in the promoters was sufficient to down-regulate the activity, the methylation by the SssI methylase had a negligible effect.…”

Section: Discussionsupporting

confidence: 77%

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Promoter Demethylation and Histone Acetylation Mediate Gene Expression of MAGE-A1, -A2, -A3, and -A12 in Human Cancer Cells

Wischnewski

Pantel

Schwarzenbach

2006

Molecular Cancer Research

161

123

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The broad range of expression of cancer-testis antigens in various tumor types makes the proteins encoded by human MAGE gene family promising targets for anticancer immunotherapy. However, a major drawback is their heterogeneous expression. In the current study, we have examined the influence of the DNA methylase inhibitor 5-aza-2 ¶-deoxycytidine (5-aza-CdR) together with the histone deacetylase inhibitor trichostatin A on the expression of MAGE-A1, -A2, -A3, and -A12 genes in different cell lines. Reverse transcription-PCR, Western blot analyses, and immunocytochemical staining show that trichostatin A was able to significantly up-regulate 5-aza-CdR-induced MAGE gene expression. Transient transfection assays with methylated reporter plasmids containing promoter fragments of the different MAGE genes show that trichostatin A was able to overcome gene silencing. In addition, the methylation status of the MAGE promoters was assessed by sodium bisulfite mapping in the various cell lines before and after stimulation with 5-aza-CdR and/or trichostatin A. In contrast to the methylation patterns, which clearly correlated with the basal MAGE RNA transcripts, up-regulation of the MAGE-A mediated by both agents only resulted in a reduction in promoter methylation ranging between 1% and 19%. In conclusion, our data show for the first time that not only hypermethylation but also histone deacetylation is responsible for the mechanism underlying MAGE gene silencing.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 77%

Promoter Demethylation and Histone Acetylation Mediate Gene Expression of MAGE-A1, -A2, -A3, and -A12 in Human Cancer Cells

Wischnewski

Pantel

Schwarzenbach

2006

Molecular Cancer Research

161

123

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“…One of the major interests in CT antigens stems from their potential use in cancer vaccines, and several of them have been used in polyvalent vaccine trials with variable success Sigalotti et al, 2002). Although the lack of humoral immunity in PDAC patients and the expression of SPAG1 in several normal tissues would probably hamper a similar utility, further studies would need to be undertaken in order to completely exclude the validity of SPAG1 in such an immunotherapeutic approach.…”

Section: Spag1 In Pancreatic Adenocarcinomamentioning

confidence: 99%

Sperm-associated antigen 1 is expressed early in pancreatic tumorigenesis and promotes motility of cancer cells

et al. 2006

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Sperm-associated antigen 1 (SPAG1) was recently identified in a rare form of infertility where anti-SPAG1 antibodies derived from the serum of an infertile woman were reported to cause sperm agglutination. Except for its expression and potential role in spermatogenesis, the function of SPAG1 is completely unknown. The unexpected finding of high levels of SPAG1 expression in pancreatic adenocarcinoma compared to normal pancreatic tissue in our previous cDNA array experiments prompted us to look in more detail at the expression and role of this gene in a panel of normal and malignant human tissues as well as in a larger series of pancreatic cancer specimens. We have generated an SPAG1-specific monoclonal antibody and showed high levels of SPAG1 protein in testis and in a large proportion of pancreatic ductal adenocarcinomas (PDAC). In the latter, SPAG1 expression was predominantly cytoplasmic and confined to malignant cells. Furthermore, the extent and intensity of SPAG1 expression was shown to be associated with stage and tumour nodal status, while analysis of precursor lesions, pancreatic intraepithelial neoplasias (PanINs), demonstrated its increased immunoreactivity with increasing PanIN grade, suggesting that SPAG1 is a novel marker of PDAC progression. Immunocytochemical analysis demonstrated colocalization of SPAG1 with microtubules, and their association was confirmed by co-immunoprecipitation; subsequent motility assays further substantiated a potential role of SPAG1 in cancer cell motility. Combined with the finding of its early expression in PDAC development, our data suggest that SPAG1 could contribute to the early spread and poor prognosis of pancreatic adenocarcinoma.

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“…These are the GAGE (G antigen 7) family (43), the MAGE (44 -48) family of melanoma antigens, and the genes residing at the synovial sarcoma X breakpoint, SSX2-4 (49,50). It is well documented that the MAGE (44 -46) and GAGE family of genes as well as SSX2 are controlled by DNA methylation and are induced by DNA-demethylating agents (51). The up-regulation of genes identified by gene array analysis was verified by semiquantitative RT-PCR shown in Fig.…”

Section: Comparison Of the Kinetics Of Demethylation Of The Tumor Supmentioning

confidence: 99%

Epigenomic Stress Response

Milutinovic

Zhuang

Niveleau

et al. 2003

Journal of Biological Chemistry

108

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The DNA methylation pattern is an important component of the epigenome that regulates and maintains gene expression programs. In this paper, we test the hypothesis that vertebrate cells possess mechanisms protecting them from epigenomic stress similar to DNA damage checkpoints. We show that knockdown of DNMT1 (DNA methyltransferase 1) by an antisense oligonucleotide triggers an intra-S-phase arrest of DNA replication that is not observed with control oligonucleotide. The cells are arrested at different positions throughout the S-phase of the cell cycle, suggesting that this response is not specific to distinct classes of origins of replication. The intra-S-phase arrest of DNA replication is proposed to protect the genome from extensive DNA demethylation that could come about by replication in the absence of DNMT1. This protective mechanism is not induced by 5-aza-2 -deoxycytidine, a nucleoside analog that inhibits DNA methylation by trapping DNMT1 in the progressing replication fork, but does not reduce de novo synthesis of DNMT1. Our data therefore suggest that the intra-S-phase arrest is triggered by a reduction in DNMT1 and not by demethylation of DNA. DNMT1 knockdown also leads to an induction of a set of genes that are implicated in genotoxic stress response such as NF-B, JunB, ATF-3, and GADD45␤ (growth arrest DNA damage 45␤ gene). Based on these data, we suggest that this stress response mechanism evolved to guard against buildup of DNA methylation errors and to coordinate inheritance of genomic and epigenomic information.Proper epigenomic regulation of gene expression is essential for the integrity of cell function. One critical component of the epigenome is the pattern of distribution of methylated cytosines in CG dinucleotide sequences in the genome (1). Methylation of CGs marks genes for inactivation by either interfering with the binding of methylated DNA-sensitive transcription factors (2) or by recruiting methylated DNA-binding proteins such as MeCP2, which in turn recruit corepressor complexes and histone deacetylases to the chromatin associated with the gene (3). The methylation pattern can thus determine the chromatin structure and state of activity of genes. Disruption in the proper maintenance of the DNA methylation pattern results in aberrant gene expression, as is observed in tumor suppressor genes that are hypermethylated in cancer (4). Aberrant hypomethylation can also result in improper activation of genes (5).The main enzyme responsible for replicating the DNA methylation pattern is DNMT1 (DNA methyltransferase 1). This enzyme shows preference for hemimethylated DNA and is therefore believed to faithfully copy the DNA methylation pattern (6). Multiple mechanisms have been proposed to coordinate the inheritance of DNA methylation patterns with DNA replication. First, DNMT1 expression is regulated with the cell cycle (7, 8), and it is up-regulated by proto-oncogenes Ras and Jun (9 -11), Fos (12), and T antigen (13). Second, DNMT1 is localized to the replication fork (14) and is associated ...

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Cancer testis antigens expression in mesothelioma: role of DNA methylation and bioimmunotherapeutic implications

Cited by 83 publications

References 18 publications

Promoter Demethylation and Histone Acetylation Mediate Gene Expression of MAGE-A1, -A2, -A3, and -A12 in Human Cancer Cells

Promoter Demethylation and Histone Acetylation Mediate Gene Expression of MAGE-A1, -A2, -A3, and -A12 in Human Cancer Cells

Sperm-associated antigen 1 is expressed early in pancreatic tumorigenesis and promotes motility of cancer cells

Epigenomic Stress Response

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