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...

The known biological activities of A1 R in brain functions including its physical interaction with and inhibitory effect on dopamine receptor D1 provide supportive evidence that disruptions of A1 R may result in neurological dysfunction. Also, recent evidence on the related adenosine A2B receptor marks the domain in which the mutation is positioned as important for function. Finally, ADORA1 is located within the Parkinson's disease locus PARK16, which has been identified in several populations. ADORA1 may be the PD susceptibility gene within this locus. The molecular mechanism by which p.Gly279Ser disrupts A1 R function remains unknown, but a quantitative effect on interaction with the dopamine receptor was not shown. © 2016 International Parkinson and Movement Disorder Society.

Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults and has but few treatments. The median survival of glioblastoma patients is 12 months. The (possible) relationship between human cytomegalovirus (HCMV) infection and cancer has been investigated for decades. Detection of viral DNA, mRNA and/or antigens in tumor tissues suggests that HCMV infection has a role to play in the etiology of several human malignancies. HCMV gene products can promote the various signaling pathways critical to tumor growth, including platelet derived growth factor receptor, phosphatidyl inositol 3-kinases (PI3K/AKT), signal transducer and activator of transcription 3 and glycogen synthase kinase 3 beta that are involved in apoptosis, angiogenesis, invasion and immune evasion. Insulin-like growth factor binding protein 2 (IGFBP2) is a biomarker of the PI3K/AKT pathway so we decided to evaluate the expression of this gene in 3 groups: HCMV-negative GBM tissues, HCMV-positive GBM tissues and non-tumor tissues. The presence of HCMV was assessed according to our previous article. HCMV was present in %75 of glioblastoma tissues. Then RNA was extracted, cDNA was synthesized, and real-time PCR was performed. Then, the rate of increased expression was calculated using the Livac or 2(-ΔΔCt). ΔCt of samples in the three groups were compared using analysis of variance (ANOVA). The expression of IGFBP2 gene relative to GAPDH gene in HCMV-negative glioblastoma tissues and HCMV-positive glioblastoma tissues, respectively, was increased 5.486 and 15.032 times compared to non-neoplastic brain tissues. ANOVA tests showed that the difference of mean ΔCt for IGFBP2 gene between healthy subjects and patients with HCMV-positive and HCMV-negative glioblastoma tumors statistically significant.

Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents.