The association between the FCER2 T2206C variant and asthma-related hospitalizations in steroid-treated asthma appears robust and may also be associated with other indicators of lack of ICS efficacy such as asthma symptoms and a requirement for higher daily doses of ICS. Our results suggest that the FCER2 T2206C variant might be a useful pharmacogenetic predictor of steroid refractory patients.
Epigenetic modifications of chromatin play an important role in differentiation, aging, and tumorigenesis (41). Major epigenetic mechanisms include DNA methylation and covalent posttranslational modification of histone tails. These events switch chromatin between relatively "open" (expressed) and "closed" (suppressed) structures. Although there are several different histone modifications, the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs) are considered important regulators of chromatin structure (28). DNA methylation is an important epigenetic modification in the vertebrate genome which occurs mainly on cytosines located in CpG dinucleotide sequences (2). DNA methylation patterns are established by DNA methyltransferase 3a (DNMT3a) and DNMT3b, which are de novo DNA methyltransferases (DNMTs), and are mainly propagated by DNMT1, a maintenance methyltransferase (39). DNA methyltransferases are involved in the aberrant DNA methylation patterns frequently found in cancer cells (21). In addition, there is growing evidence that inappropriate gene expression by epigenetic events is crucial for the initiation and progression of cancer. These epigenetic abnormalities, including epigenetic silencing of tumor suppressor genes by abnormal promoter methylation, are likely to play an important role in tumor growth and metastasis when a substantial number of genes can be inactivated by DNA methylation in a tumor (20). In addition to DNA methylation, genome-wide changes in histone modifications are also found in cancer cells. Loss of acetylation at lysine 16 and trimethylation at lysine 20 of histone H4 have been reported as common hallmarks of human cancer (11).New insights into the high prevalence of epigenetic changes in cancer have led to novel therapeutic approaches in oncology that rely on the dynamic nature of epigenetic factors. The main idea behind these approaches is that abnormal epigenetic marks leading to gene silencing may be reversed. Two categories of drugs, affecting histone acetylation and DNA methylation, are currently considered in epigenetic therapy of cancer. In myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) are already in clinical use (15,23). HDACi can open up chromatin by causing hyperacetylation of histones H3 and H4 (49). DNMTi, such as 5-aza-deoxycytidine, can induce genomic DNA hypomethylation (35). However, some gene promoters are not readily activated with either of the two inhibitors alone, but there are reports showing that HDACi and DNMTi can act synergistically to reactivate silenced genes (12,47). Therefore, the functional interaction between HDACs and DNMTs has been a key issue in epigenetic research. Trichostatin A (TSA), a general inhibitor for class I and II HDACs, has also been shown to reactivate methylation-silenced genes even in the absence of DNMT inhibitors (25). In addition, it has been reported that TSA decreases DNMT3b mRNA levels in endo...
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