The epigenetics orchestra of Notch signaling: a symphony for cancer therapy.

The aberrant regulation of the Notch signaling pathway, which is a fundamental developmental pathway, has been implicated in a wide range of human cancers. The Notch pathway can be activated by both canonical and noncanonical Notch ligands, and its role can switch between acting as an oncogene or a tumor suppressor depending on the context. Epigenetic modifications have the potential to modulate Notch and its ligands, thereby influencing Notch signal transduction. Consequently, the utilization of epigenetic regulatory mechanisms may present novel therapeutic opportunities for both single and combined therapeutics targeted at the Notch signaling pathway. This review offers insights into the mechanisms governing the regulation of Notch signaling and explores their therapeutic potential.

Insights into the Links between MYC and 3D Chromatin Structure and Epigenetics Regulation: Implications for Cancer Therapy.

MYC is embedded in the transcriptional oasis of the 8q24 gene desert. A plethora of genomic elements has roles in MYC aberrant expression in cancer development by interacting with transcription factors and epigenetics regulators as well as altering the structure of chromatin at the MYC locus and tissue-specific long-range enhancer-promoter contacts. Furthermore, MYC is a master regulator of several human cancers by modulating the transcription of numerous cancer-related genes through epigenetic mechanisms. This review provides a comprehensive overview of the three-dimensional genomic organization around MYC and the role of epigenetic machinery in transcription and function of MYC as well as discusses various epigenetic-targeted therapeutic strategies in MYC-driven cancers.

PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond.

PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers. Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.

Wnt signaling pathway in osteoporosis: Epigenetic regulation, interaction with other signaling pathways, and therapeutic promises.

Wnt is a major signaling pathway involved in multifaceted roles of various biological processes. Bones are dynamic tissues which are able to remodel and maintain the tissue homeostasis. Wnt signaling cascade leads to the promotion of bone formation and suppression of bone resorption, leading to a balance in bone remodeling. Recent evidence has reinforced the inevitable role of Wnt signaling in osteoporosis. The complex genetic and epigenetic regulations of Wnt signaling factors and their interaction with other master signaling pathways such as TGF-ß, BMP, PI3K/AKT, and Hedgehog outline their importance in diagnosis and treatment of osteoporosis. In this review, we highlighted the recent advances in function of Wnt signaling-related epigenetic regulation, different signaling pathways interacting with Wnt, and their roles in osteoporosis. Finally, we discussed novel promises in molecular targeted therapy of osteoporosis.

Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections.

Gastric cancer (GC) is one of the most common causes of cancer-related death in the world, with multiple genetic and epigenetic alterations involved in disease development. CYLD tumor suppressor gene encodes a multifunctional deubiquitinase which negatively regulates various signaling pathways. Deregulation of this gene has been found in different types of cancer. This study aimed to evaluate for the first time the CpG island methylation pattern of CYLD gene promoter, and its expression level in gastric adenocarcinoma. CYLD messenger RNA expression and promoter methylation in 53 tumoral and their non-neoplastic counterpart tissues were assessed using quantitative polymerase chain reaction and bisulfite sequencing. Also, we investigated the impacts of the infectious agents including Helicobacter pylori (H. pylori), EBV, and CMV on CYLD expression and promoter methylation in GC. Results showed that the expression level of CYLD was downregulated in GC, and was significantly associated with gender (female), patient's age (<60), high grade, and no lymph-node metastasis (p = 0.001, 0.002, 0.03, and 0.003, respectively). Among the 31 analyzed CpG sites located in about 600 bp region within the promoter, two CpG sites were hypermethylated in GC tissues. We also found a significant inverse association between DNA promoter methylation and CYLD expression (p = 0.02). Furthermore, a direct association between H. pylori, EBV, and CMV infections with hypermethylation and reduced CYLD expression was observed (p = 0.04, 0.03, and 0.03, respectively). Our findings indicate that CYLD is downregulated in GC. Infectious agents may influence CYLD expression.

CTNNBIP1 downregulation is associated with tumor grade and viral infections in gastric adenocarcinoma.

Gastric cancer is a life-threatening disease; resulting from interaction among genetic, epigenetic, and environmental factors. Aberrant dysregulation and methylation changes in Wnt/ß-catenin signaling downstream elements are a prevalent phenomenon encountered in gastric tumorigenesis. Also, viral infections play a role in gastric cancer development. CTNNBIP1 (ß-catenin interacting protein 1) gene is an antagonist of Wnt signaling which binds to the ß-catenin molecules. The CTNNBIP1 function as tumor suppressor gene or oncogene in different types of cancer is controversial. Moreover, its function and regulatory mechanisms in gastric cancer progression is unknown. In the present study, we examined CTNNBIP1 gene expression, the methylation status of the regulatory region of the gene, and their association with Epstein-Barr virus (EBV), and cytomegalovirus (CMV) and Helicobacter pylori infections in human gastric adenocarcinoma tissues in comparison with their adjacent nontumoral tissues. Our data revealed a significant downregulation of CTNNBIP1 in gastric tumors. Female patients showed lower level of CTNNBIP1 than males (p < 0.05). Also, decreased expression of CTNNBIP1 was markedly associated with well-differentiated tumor grades (p < 0.05). No methylation change was observed between tumoral and nontumoral tissues. Additionally, CTNNBIP1 down regulation was significantly associated with CMV infection (p < 0.05). In the absence of EBV infection, lower expression of CTNNBIP1 was observed. There was no association between H. pylori infection and CTNNBIP1 expression. Our findings revealed the tumor suppressor role for CTNNBIP1 in gastric adenocarcinoma. Interestingly, EBV and CMV infections modulate CTNNBIP1 expression.

Informative combination of CLU rs11136000, serum HDL levels, diabetes, and age as a new piece of puzzle-picture of predictive medicine for cognitive disorders.

Clusterin (CLU) is the third most important associated risk gene in cognitive disorders. Regarding the controversy about the association of CLU rs11136000 with mild cognitive impairment (MCI), the aim of this study was to investigate a putative association of CLU rs11136000 with MCI as well as the serum biological factors with a special attention to the age as a main dimension of a multifactorial elderly disease in an Iranian elderly cohort in which the mentioned association was not previously investigated. The study also checked the association between diabetes and MCI in this population. A population of 418 individuals containing 236 MCI and 192 control subjects was recruited from the Amirkola health and aging population cohort. Serum biological indexes were assessed by biochemical and enzyme-linked immunosorbent assay, and rs11136000 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. Bioinformatics analyses were used to identify the putative effect of rs11136000 on the secondary structure of RNA and chromatin location in different cell lines and tissues. Type 2 diabetes was present with a higher proportion in the MCI group in comparison with the control group (P = 0.041). The frequency of the C allele of CLU rs11136000 was significantly different between cases and controls and was associated with MCI risk (OR 1.79, P = 0.019). Under a dominant genetic model, the CC genotype showed a predisposing effect in individuals aged ≥ 75 years (OR 3.33, P = 0.0004). Interestingly, under an over-dominant model, the CT genotype had a protective effect in this population (OR 4.52, P = < 0.0001). We also found a significant association between the genotypes and high-density lipoprotein (HDL) levels in MCI patients (P = 0.0004). Bioinformatics analysis showed that rs11136000 is located in the transcribed region without any regulatory features such as being enhancer or insulator. Also, the T>C transition of CLU rs11136000 could not cause significant mRNA folding (P = 0.950). Contrary to other studies on Asian populations, this study demonstrated an association between rs11136000 and MCI in an elderly Iranian population. This study also suggests that an age-dependent approach to the previous studies may be performed in order to revise the previous belief in this geographical area. The rs11136000 genotypes in combination with HDL levels and knowledge about diabetes background may be used as a predictive medicine tool for cognitive disorders.

DNA methyltransferases and gastric cancer: insight into targeted therapy.

Gastric cancer is a major health problem worldwide occupying most frequent causes of cancer-related mortality. In addition to genetic modifications, epigenetic alterations catalyzed by DNA methyltransferases (DNMTs) are a well-characterized epigenetic hallmark in gastric cancer. The reversible nature of epigenetic alterations and central role of DNA methylation in diverse biological processes provides an opportunity for using DNMT inhibitors to enhance the efficacy of chemotherapeutics. In this review, we discussed key factors or mechanisms such as SNPs, infections and genetic modifications that trigger DNMTs level modification in gastric cancer, and their potential roles in cancer progression. Finally, we focused on how inhibitors of the DNMTs can most effectively be used for the treatment of gastric cancer with multidrug resistance.

A specific haplotype in potential miRNAs binding sites of secreted frizzled-related protein 1 (SFRP1) is associated with BMD variation in osteoporosis.

PURPOSE: Osteoporosis is an important multifactorial disease which is largely influenced by Wnt signaling pathway. Considering regulatory single nucleotide polymorphisms in Wnt signaling pathway may pave the road of understanding the genetic basis of predisposition to osteoporosis. The aim of this study was to determine the possible association between variants of SFRP1 and WNT5b, and osteoporosis incidence risk. METHODS: The study population comprised 186 osteoporotic patients and 118 normal subjects from Amirkola Health and Ageing Project. rs1127379 (c.1406A>G) and rs3242 (c.3132C>T) variants in 3'UTR of SFRP1 gene, and rs3803164 (c.236C>T) in 3'UTR and rs735890 (c.622-536A>G) in intron 4 of WNT5b gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Regression analyses were used to calculate the association of genotype frequencies with bone mineral density (BMD) and bone mineral content (BMC) values of participants. Bioinformatics algorithms were used to detect the effect of each SNP on the secondary structure of mRNA, and predict putative 3'UTR microRNA target sites and splicing sites changes by related SNPs. RESULTS: WNT5b rs735890 was associated with lumbar spine BMD, BMC, and femoral neck BMC (P = 0.035, P = 0.007, and P = 0.038, respectively). WNT5b rs3803164, and SFRP1 rs3242 were significantly associated with lumbar spine BMD (P = 0.028 and P = 0.030, respectively). SFRP1 rs1127379 was associated with lumbar spine BMD in the male gender. Haplotype analysis showed a significant association of SFRP1 c.[1406A; 3132C] haplotype with lumbar spine BMD, and BMC (P = 0.019 and P = 0.030, respectively), and SFRP1 c.[1406G; 3132C] haplotype with lumbar spine BMC (P = 0.045). In silico analyses revealed that the G allele of SFRP1 rs1127379, and WNT5b rs3803164 appear as more possible target sites for many miRNAs. CONCLUSIONS: This study is the first evidence of the association of WNT5b rs735890, and c.[1406A; 3132C] and c.[1406G; 3132C] haplotypes of SFRP1 with BMD variation in osteoporosis, probably by altering microRNA target sites, in elderly persons.

Association of interleukin-6 (rs1800796) but not transforming growth factor beta 1 (rs1800469) with serum calcium levels in osteoporotic patients.

BACKGROUND: Osteoporosis is a multifactorial disease with a strong genetic influence. Recent studies have demonstrated that cytokines, such as TGF-ß1 and interleukin 6 (IL-6) play complex roles in the normal bone metabolism and pathophysiology of osteoporosis. Here, we investigated the roles of 2 polymorphisms mapping to the promoters of TGF-ß1and IL-6 genes on the genetic susceptibility to osteoporosis as well as calcium and vitamin D levels. METHODS: A cohort of 297 elderly participants in northern Iran comprising 181 osteoporotic patients (mean age ±â€¯SD, 68.36 ±â€¯7.21 years) and 116 unrelated healthy controls (mean age ±â€¯SD, 64 ±â€¯5.44 years) was studied for TGF-ß1(C-509T) and IL-6 (G-634C) polymorphisms using PCR-RFLP method. RESULTS: A significant relationship was observed between calcium level and IL-6 genotypes in osteoporotic males (P = 0.011) and females (P = 0.020). No significant differences were observed between osteoporotic and control groups with respect to allele frequency or genotype distribution based on the 2 selected polymorphisms under different genetic models. The results remained the same after comparing the BMD values of either the femur neck or lumbar spine with the genotypes of the elderly men and women when analyzed separately. CONCLUSION: IL-6 genotype influences serum calcium levels in osteoporotic patients. The lack of association between the common genetic variations of TGF-ß1 and IL-6 genes, and BMD highlights the complex genetic background of osteoporosis in the north of Iran.