ABSTRACT
Epstein-Barr virus (EBV) microRNAs (miRNAs) are expressed in EBV-associated tumors and cell lines, but the regulation mechanism of their expression is unclear yet. We investigated whether the expression of EBV miRNAs is epigenetically regulated in EBV-infected B cell lines. The expression of BART miRNAs was inversely related with the methylation level of the BART promoter at both steady-state and following 5-aza-2'-deoxycytidine treatment of the cells. The expression of BHRF1 miRNAs also became detectable with the demethylation of Cp/Wp in latency I EBV-infected cell lines. Furthermore, in vitro methylation of the BART and Cp promoters reduced the promoter-driven transactivation. In contrast, tricostatin A had little effect on the expression of EBV miRNA expression as well as on the BART and Cp/Wp promoters. Our results suggest that promoter methylation, but not histone acetylation, plays a role in regulation of the EBV miRNA expression in EBV-infected B cell lines.
Subject(s)
Humans , Azacitidine/analogs & derivatives , B-Lymphocytes/metabolism , Cell Line , DNA Methylation , DNA Modification Methylases/antagonists & inhibitors , Gene Expression Regulation, Viral , Gene Silencing , Herpesvirus 4, Human/genetics , MicroRNAs/genetics , Promoter Regions, Genetic , RNA, Viral/genetics , Viral Proteins/geneticsABSTRACT
DNA methyltransferase inhibitor, 5-azacitidine (AC) is effective in myelodysplastic syndromes (MDS) and can induce re-expression in cancer. We analyzed the methylation of 25 tumor suppressor genes in AC-treated MDS. Hypermethylation of CDKN2B, FHIT, ESR1, and IGSF4 gene was detected in 9/44 patients. In concordance with the clinical response, a lack of or decreased methylation in 4 patients with hematologic improvements and persistent methylation in 4 others with no response was observed. The mRNA expression of CDKN2B, IGSF4, and ESR1 was significantly reduced in MDS. Our results suggest that methylation changes contribute to disease pathogenesis and may serve as marker to monitor the efficacy of treatments.
Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Azacitidine/pharmacology , DNA Methylation/drug effects , DNA Modification Methylases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Genes, Tumor Suppressor , Myelodysplastic Syndromes/drug therapyABSTRACT
Epigenetics, heritable changes in gene expression that do not involve changes in DNA sequence, is known to be involved in disease. Two important epigenetic changes that are known to contribute to disease are abnormal methylation patterns of DNA and modifications of histones in chromatin. This review describes a new development in pharmacology, epigenetic therapy, which attempts to correct these changes. At present two groups of drugs are being developed. One inhibits DNA methyltransferases (DNMTs) resulting in the inhibition of DNA methylation. This group of drugs may prove to be useful in the treatment of cancer where hypermethylation of tumour suppressor genes is known to lead to silencing of these genes. The other group of drugs inhibits histone deacetylases (HDACs) resulting in the accumulation of acetylated histones which are thought to mediate the anticancer effects of these drugs. Both these drug groups have shown promising results in drug trials for the treatment of cancer. Since epigenetic changes are thought to underlie a wide range of diseases, the scope of epigenetic therapy is likely to expand.