Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer testis antigens (CTAs) are promising targets for T cell-based immunotherapy and studies have shown that certain CT genes are epigenetically depressed in cancer cells through DNA demethylation. Melanoma-associated antigen A11 (MAGE-A11) is a CTA that is frequently expressed in esophageal cancer and is correlated with a poor esophageal cancer prognosis. Consequently, MAGE-A11 is a potential immunotherapy target. In this study, we evaluated MAGE-A11 expression in esophageal cancer cells and found that it was downregulated in several tumor cell lines, which restricted the effect of immunotherapy. Additionally, the specific recognition and lytic potential of cytotoxic T lymphocytes (CTLs) derived from the MAGE-A11 was determined. Specific CTLs could kill esophageal cancer cells expressing MAGE-A11 but rarely lysed MAGE-A11-negative tumor cells. Therefore, induction of MAGE-A11 expression is critical for CTLs recognition and lysis of esophageal cancer cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased MAGE-A11 expression in esophageal cancer cells and subsequently enhanced the cytotoxicity of MAGE-A11-specific CD8+T cells against cancer cell lines. Furthermore, we found that PD-L1 expression in esophageal cancer cells affected the antitumor function of CTLs. programmed death-1 (PD-1)/PD-L1 blockade could increase the specific CTL-induced lysis of HLA-A2+/MAGE-A11+ tumor cell lines treated with 5-aza-2'-deoxycytidine. These findings indicate that the treatment of tumor cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine augments MAGE-A11 expression in esophageal cancer cells. The combination of epigenetic modulation by 5-aza-2'-deoxycytidine and PD-1/PD-L1 blockade may be useful for T cell-based immunotherapy against esophageal cancer.
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PMID:Epigenetic modulation combined with PD-1/PD-L1 blockade enhances immunotherapy based on MAGE-A11 antigen-specific CD8+T cells against esophageal carcinoma. 3252 60

The transcriptional activity of genes encoding cancer/testis antigens (CTA) and its regulation in colorectal cancer (CRC) is not well understood. The expression of CTA coding genes (CT genes) and possible mechanisms for its regulation, including expression and copy number of DNA methyltransferase genes, copy number of CT genes, microRNA expression, and LINE-1 methylation in CRC were analyzed in this study. The relative expression levels and copy number variation of 19 genes, MAGE-A1, -A2, -A3, -A4, -B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NY-ESO1, SSX2, SCP1, PRAME1, DNMT1, DNMT3A, and DNMT3B, were determined using real-time quantitative PCR. Quantitative methylation of LINE-1 CpG sites was evaluated by pyrosequencing, and multiple parallel sequencing was used to determine the level of microRNA expression. It was found that in colon tumor tissue a multidirectional destabilization of the transcriptional activity of DNMT3A and DNMT3B, associated with copy number variation and a change in expression of the CT genes BAGE, SSX2 and PRAME1, is observed. A strong positive correlation was found between copy number and expression of the BAGE, SSX2, and PRAME1 genes. As a result of multiple parallel sequencing, 6 differentially expressed microRNAs (hsa-miR-143-3p, hsa-miR-26a-5p, hsa-miR-25-3p, hsa-miR-92a-3p, hsa-miR-21-5p, and hsa-let-7i-5p), targeting the CT genes GAGE1, SSX2, PRAME, SCP1, and the gene for DNA methyltransferase 3A (DNMT3A), were found. Data on the mechanisms of the transcriptional activity regulation of CT genes in malignant colon tumors are important for the development of CTA-dependent immunotherapeutic approaches for the treatment of this type of tumor.
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PMID:[Regulation of Gene Expression of Cancer/Testis Antigens in Colorectal Cancer Patients]. 3279 21


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