DNA Methylation Pattern as Important Epigenetic Criterion in Cancer

Epigenetic modifications can affect the long-term gene expression without any change in nucleotide sequence of the DNA. Epigenetic processes intervene in the cell differentiation, chromatin structure, and activity of genes since the embryonic period. However, disorders in genes' epigenetic pattern can affect the mechanisms such as cell division, apoptosis, and response to the environmental stimuli which may lead to the incidence of different diseases and cancers. Since epigenetic changes may return to their natural state, they could be used as important targets in the treatment of cancer and similar malignancies. The aim of this review is to assess the epigenetic changes in normal and cancerous cells, the causative factors, and epigenetic therapies and treatments

The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been known to be involved in cell growth, cellular differentiation processes development, immune cell survival, and hematopoietic system development. As an important member of the STAT family, STAT3 participates as a major regulator of cellular development and differentiation-associated genes. Prolonged and persistent STAT3 activation has been reported to be associated with tumor cell survival, proliferation, and invasion. Therefore, the JAK-STAT pathway can be a potential target for drug development to treat human cancers, e.g., hematological malignancies. Although STAT3 upregulation has been reported in hematopoietic cancers, protein-level STAT3 mutations have also been reported in invasive leukemias/lymphomas. The principal role of STAT3 in tumor cell growth clarifies the importance of approaches that downregulate this molecule. Epigenetic modifications are a major regulatory mechanism controlling the activity and function of STAT3. So far, several compounds have been developed to target epigenetic regulatory enzymes in blood malignancies. Here, we discuss the current knowledge about STAT3 abnormalities and carcinogenic functions in hematopoietic cancers, novel STAT3 inhibitors, the role of epigenetic mechanisms in STAT3 regulation, and targeted therapies, by focusing on STAT3-related epigenetic modifications

Promoter methylation and expression pattern of DLX3, ATF4, and FRA1 genes during osteoblastic differentiation of adipose-derived mesenchymal stem cells

Introduction: Nowadays, mesenchymal stem cells are touted as suitable cell supply for the restoration of injured bone tissue. The existence of osteogenic differentiation makes these cells capable of replenishing damaged cells in the least possible time. It has been shown that epigenetic modifications, especially DNA methylation, contribute to the regulation of various transcription factors during phenotype acquisition. Hence, we concentrated on the correlation between the promoter methylation and the expression of genes DLX3, ATF4, and FRA1 during osteoblastic differentiation of adipose-derived mesenchymal stem cells in vitro after 21 days. Methods: Adipose-derived mesenchymal stem cells were cultured in osteogenesis differentiation medium supplemented with 0.1 µM dexamethasone, 10 mM β-glycerol phosphate, and 50 µM ascorbate-2-phosphate for 21 days. RNA and DNA extraction was done on days 0, 7, 14, and 21. Promoter methylation and expression levels of genes DLX3, ATF4, and FRA1 were analyzed by methylation-specific quantitative PCR and real-time PCR assays, respectively. Results: We found an upward expression trend with the increasing time for genes DLX3, ATF4, and FRA1 in stem cells committed to osteoblast-like lineage compared to the control group (P<0.05). On the contrary, methylation-specific quantitative PCR displayed decreased methylation rates of DLX3 and ATF4 genes, but not FRA1, over time compared to the non-treated control cells (P<0.05). Bright-field images exhibited red-colored calcified deposits around Alizarin Red S-stained cells after 21 days compared to the control group. Statistical analysis showed a strong correlation between the transcription of genes DLX3 and ATF4 and methylation rate (P<0.05). Conclusion: In particular, osteoblastic differentiation of adipose-derived mesenchymal stem cells enhances DLX3 and ATF4 transcriptions by reducing methylation rate for 21 days

Epigenetic mechanisms as a new approach in cancer treatment: An updated review

Epigenetic, along with genetic mechanisms, is essential for natural evolution and maintenance of specific patterns of gene expression in mammalians. Global epigenetic variation is inherited somatically and unlike genetic variation, it is dynamic and reversible. They are somatically associated with known genetic variations.Recent studies indicate the broad role of epigenetic mechanisms in the initiation and development of cancers, that they are including DNA methylation, histone modifications, nucleosomes changes, non-coding RNAs. The reversible nature of epigenetic changes has led to the emergence of novel epigenetic therapeutic approaches, so that several types of these medications have been approved by the FDA so far.In this review, we discuss the concept of epigenetic changes in diseases, especially cancers, the role of these changes in the onset and progression of cancers and the potential of using this knowledge in designing novel therapeutic strategies. Keywords: Cancer, Epigenetic, Mechanisms, Treatment, Methylatio

Neoplastic Bone Marrow Niche: Hematopoietic and Mesenchymal Stem Cells

The neoplastic niche comprises complex interactions between multiple cell typesand molecules requiring cell-cell signaling as well as local secretion. These nichesare important for both the maintenance of cancer stem cells and the inductionof neoplastic cells survival and proliferation. Each niche contains a population oftumor stem cells supported by a closely associated vascular bed comprising mesenchyme-derived cells and extracellular matrix. Targeting cancer stem cells andneoplastic niche may provide new therapies to eradicate tumors. Much progresshas been very recently made in the understanding of the cellular and molecularinteractions in the microenvironment of neoplastic niches. This review articleprovides an overview of the neoplastic niches in the bone marrow. In addition tohighlighting recent advances in the field, we will also discuss components of theniche and their signaling pathways

DNA Methylation Pattern as Important Epigenetic Criterion in Cancer

Epigenetic modifications can affect the long-term gene expression without any change in nucleotide sequence of the DNA. Epigenetic processes intervene in the cell differentiation, chromatin structure, and activity of genes since the embryonic period. However, disorders in genes’ epigenetic pattern can affect the mechanisms such as cell division, apoptosis, and response to the environmental stimuli which may lead to the incidence of different diseases and cancers. Since epigenetic changes may return to their natural state, they could be used as important targets in the treatment of cancer and similar malignancies. The aim of this review is to assess the epigenetic changes in normal and cancerous cells, the causative factors, and epigenetic therapies and treatments

Molecular Mechanisms of Hemoglobin F Induction

Hemoglobin F (HbF, α2γ2) is a major contributor to the clinical heterogeneity and ameliorating agent observed in patients with the β-globin disorders including β-thalassemia and sickle cell disease (SCD). During fetal life, HbF is the major hemoglobin but is largely substituted by adult hemoglobin (HbA, α2β2) following a globin expression switch after birth. Increased γ-globin expression can reduce the clinical severity of β-thalassemia and SCD. Therefore, increase in HbF production has served as a longstanding goal. The progression of target-based therapeutics has been confused by limited comprehension of molecular mechanisms of gamma-globin gene expression. However, recent discoveries of regulators of HbF level represent a major development and provide new opportunities in employing novel rational therapeutic strategies. In this review, molecular mechanisms of hemoglobin F induction will be discussed

Cytochrome P4502C19*3 allelic variant frequency in Iranian healthy Azeri Turkish population

Introduction: Cytochrome P4502C19 (CYP2C19) is well-known to be one of the determinants responsible for the pronounced interethnic and individual differences in response and character of clinically important drugs. CYP2C19*3 arises from a G to A transition at position 636 in exon 4 of CYP2C19. These individuals be situated poor metabolizers (PMs) of a wide range of medications including omeprazole (OMP). In this study, we determined genotypes of CYP2C19*3 in Iranian Azeri Turkish population to compare allele frequencies with previous findings in other ethnic groups. Methods: CYP2C19*3 allelic variant was determined in 200 unrelated healthy Iranian volunteers by polymerase chain reaction-restriction fragment length polymorphism assays (PCR-RFLP). Results: The frequencies of CYP2C19*3 in healthy volunteers reported in this study (P = 0.569, χ2 = 2.35). This is not higher than that would be predicted from the genotypic status of these cases in CYP2C19*3 allelic variants. Our results revealed that 95.46% had wild type allele, they did not carry any of the tested mutations and 9 (4.54%) had mutant alleles. Conclusion: Our data recommend that genotyping for CYP2C19*3 is interest in using pharmacokinetics to individualize medicine, but results of this study demonstrated that CYP2C19*3 genetic polymorphism is not important determinant of the efficacy of PM of drugs, such as OMP, which may be metabolized by this enzyme

ROR2 Promoter Methylation Change in Osteoblastic Differentiation of Mesenchymal Stem Cells

Objective: Osteoblasts arise from multipotent mesenchymal stem cells (MSCs) presentin the bone marrow stroma and undergo further differentiation to osteocytes or bone cells.Many factors such as proteins present in the Wnt signaling pathway affect osteoblastdifferentiation. ROR2 is an orphan tyrosine kinase receptor that acts as a co-receptor inthe non-canonical Wnt signaling pathway. However, ROR2 has been shown to be regulatedby both canonical and non-canonical Wnt signaling pathways. ROR2 expressionincreases during differentiation of MSCs to osteoblasts and then decreases as cells differentiateto osteocytes. On the other hand, research has shown that ROR2 changesMSC fate towards osteoblasts by inducing osteogenic transcription factor OSTERIX. Herewe speculated whether ROR2 gene expression regulation during osteoblastogenesis isepigenetically determined.Materials and Methods: MSCs from bone marrow were isolated, expanded and characterizedin vitro according to standard procedures. ROR2 promoter methylation status wasdetermined using methylation specific PCR in a multipotent state and during differentiationto osteoblasts.Results: We determined that the demethylation process in ROR2 promoter occurs duringthe differentiation process. The process of demethylation begins at day 8 and continuesuntil 21 days of differentiation.Conclusion: This result is in concordance with previous works on the role of ROR2 onosteoblast differentiation, which have shown an upregulation of ROR2 expression duringthis process

The effect of resveratrol on the expression of MDR1 gene in leukemic lymphoblast’s of acute lymphoblastic leukemia patients

Background: Chemotherapy plays a very important role in the treatment of leukemia but the resistance properties of the lymphoblasts limit the effect of chemotherapy. One of the main mechanisms of resistance to chemotherapy is the increased expression of MDR1 gene. The aim of this study was to explore the effect of resveratrol on the expression of MDR1 gene in leukemic lymphoblast of new cases of acute lymphoblastic leukemia (ALL) patients in vitro. Methods: Separation of lymphoblasts of 5 new case ALL patients from peripheral blood was performed by ficoll density gradient centrifugation. Lymphoblasts were cultured in RPMI 1640 medium. Lymphoblasts were treated with 50µmol/L resveratrol for 48 h. Total RNA was extracted with guanidine isothiocyanate. RNA was converted to cDNA. Real time PCR was used to detect mRNA expression of MDR1. Results: The results of gene detection showed that the expression of MDR1 did not change significantly in the patients however, in one patient expression of MDR1 increased upon treatment with resveratrol. Conclusion: The results of this study did not support resveratrol as a compound to reverse multidrug resistance in leukemic lymphoblasts