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Biochimica Et Biophysica Acta.... Jan 2023DNA methylation profiles are in dynamic equilibrium via the initiation of methylation, maintenance of methylation and demethylation, which control gene expression and... (Review)
Review
DNA methylation profiles are in dynamic equilibrium via the initiation of methylation, maintenance of methylation and demethylation, which control gene expression and chromosome stability. Changes in DNA methylation patterns play important roles in carcinogenesis and primarily manifests as hypomethylation of the entire genome and the hypermethylation of individual loci. These changes may be reflected in blood-based DNA, which provides a non-invasive means for cancer monitoring. Previous blood-based DNA detection objects primarily included circulating tumor DNA/cell-free DNA (ctDNA/cfDNA), circulating tumor cells (CTCs) and exosomes. Researchers gradually found that methylation changes in peripheral blood mononuclear cells (PBMCs) also reflected the presence of tumors. Blood-based DNA methylation is widely used in early diagnosis, prognosis prediction, dynamic monitoring after treatment and other fields of clinical research on cancer. The reversible methylation of genes also makes them important therapeutic targets. The present paper summarizes the changes in DNA methylation in cancer based on existing research and focuses on the characteristics of the detection objects of blood-based DNA, including ctDNA/cfDNA, CTCs, exosomes and PBMCs, and their application in clinical research.
Topics: Humans; DNA Methylation; Leukocytes, Mononuclear; Biomarkers, Tumor; Circulating Tumor DNA; Neoplasms; Cell-Free Nucleic Acids
PubMed: 36270476
DOI: 10.1016/j.bbadis.2022.166583 -
Cell Death Discovery Apr 2024Corneal diseases are among the primary causes of blindness and vision loss worldwide. However, the pathogenesis of corneal diseases remains elusive, and diagnostic and... (Review)
Review
Corneal diseases are among the primary causes of blindness and vision loss worldwide. However, the pathogenesis of corneal diseases remains elusive, and diagnostic and therapeutic tools are limited. Thus, identifying new targets for the diagnosis and treatment of corneal diseases has gained great interest. Methylation, a type of epigenetic modification, modulates various cellular processes at both nucleic acid and protein levels. Growing evidence shows that methylation is a key regulator in the pathogenesis of corneal diseases, including inflammation, fibrosis, and neovascularization, making it an attractive potential therapeutic target. In this review, we discuss the major alterations of methylation and demethylation at the DNA, RNA, and protein levels in corneal diseases and how these dynamics contribute to the pathogenesis of corneal diseases. Also, we provide insights into identifying potential biomarkers of methylation that may improve the diagnosis and treatment of corneal diseases.
PubMed: 38589350
DOI: 10.1038/s41420-024-01935-2 -
Drug Design, Development and Therapy 2016Lung cancer is the leading cause of cancer-related mortality in men worldwide. Aberrant RARβ promoter methylation has been frequently investigated in non-small-cell... (Meta-Analysis)
Meta-Analysis Review
Lung cancer is the leading cause of cancer-related mortality in men worldwide. Aberrant RARβ promoter methylation has been frequently investigated in non-small-cell lung carcinoma (NSCLC), the most common form of lung cancer. The aim of present study was to carry out a meta-analysis and a systematic review to evaluate clinicopathological significance of RARβ promoter hypermethylation in NSCLC. A systematic literature search was carried out. The data were extracted and assessed by two reviewers independently. The Cochrane software Review Manager 5.2 was used to conduct the review. Odds ratios (ORs) with 95% corresponding confidence intervals (CIs) were calculated. A total of 18 relevant articles were available for meta-analysis which included 1,871 participants. The frequency of RARβ hypermethylation was significantly increased in NSCLC than in nonmalignant lung tissue, and the pooled OR was 5.69 (P<0.00001). RARβ hypermethylation was significantly more frequently observed in adenocarcinoma (AC) than in squamous cell carcinoma (SCC), and the pooled OR was 1.47 (P=0.005). Hypermethylation of RARβ gene in NSCLC was 2.46 times higher in smoking than in nonsmoking individuals, and the pooled OR was 2.46 (P=0.0002). RARβ hypermethylation rate was not significantly correlated with stage of the disease and sex. RARβ gene methylation status was not associated with prognosis of patients with NSCLC. In conclusion, RARβ promoter hypermethylation significantly increased in NSCLC than in non-neoplastic lung tissue and is predominant in AC, suggesting that RARβ methylation contributes to the development of NSCLC, especially AC. RARβ gene is a potential novel target for development of personalized therapy in patients with NSCLC, and is promising in restoration of retinoic acid-target gene induction via demethylation of RARβ1' promoter.
Topics: Carcinoma, Non-Small-Cell Lung; DNA Methylation; Humans; Lung Neoplasms; Molecular Targeted Therapy; Promoter Regions, Genetic; Receptors, Retinoic Acid
PubMed: 27103788
DOI: 10.2147/DDDT.S96766 -
Cancer Treatment Reviews Mar 2017It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the treatment of haematological malignancies. Based on encouraging preclinical results, demethylating agents may also be effective in solid tumours. This systematic review summarizes the evidence of the effect of demethylating agents on clinical response, methylation and the immune system in solid tumours.
METHODS
We conducted a systematic literature search from 1949 to December 2016, according to the PRISMA guidelines. Studies which evaluated treatment with azacitidine, decitabine, guadecitabine, hydralazine, procaine, MG98 and/or zebularine in patients with solid tumours were included. Data on clinical response, effects on methylation and immune response were extracted.
RESULTS
Fifty-eight studies were included: in 13 studies complete responses (CR) were observed, 35 studies showed partial responses (PR), 47 studies stable disease (SD) and all studies except two showed progressive disease (PD). Effects on global methylation were observed in 11/15 studies and demethylation/re-expression of tumour specific genes was seen in 15/17 studies. No clear correlation between (de)methylation and clinical response was observed. In 14 studies immune-related responses were reported, such as re-expression of cancer-testis antigens and upregulation of interferon genes.
CONCLUSION
Demethylating agents are able to improve clinical outcome and alter methylation status in patients with solid tumours. Although beneficial effect has been shown in individual patients, overall response is limited. Further research on biomarker predicting therapy efficacy is indicated, particularly in earlier stage and highly methylated tumours.
Topics: Antimetabolites, Antineoplastic; Azacitidine; Cytidine; DNA Methylation; Decitabine; Humans; Hydralazine; Immune System; Methylation; Neoplasms; Procaine; Treatment Outcome
PubMed: 28189913
DOI: 10.1016/j.ctrv.2017.01.004 -
Oncotarget Jan 2017Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and then to 5-formylcytosine (5-fC) and... (Meta-Analysis)
Meta-Analysis Review
Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and then to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), resulting in genomic DNA demethylation. Decreased 5-hmC levels have been reported in a variety of cancers, and loss of 5-hmC might be considered an epigenetic hallmark of cancer. However, the prognostic value of decreased 5-hmC in cancers remain controversial. Here, a systematic review was performed by conducting an electronic search of PubMed, EMBASE, Web of Science and the Cochrane Library. Finally, ten studies with a total of 1736 patients with cancer were included in the present study. Negative/low 5-hmC levels were significantly associated with lymph node metastasis [OR=2.20, 95% CI=1.23-3.96, P=0.008] and advanced TNM stage [OR=2.89, 95% CI=1.21-6.92, P=0.017]. More importantly, negative/low 5-hmC levels were significantly associated with poor prognosis of cancer patients [overall survival: HR=1.76, 95% CI=1.41-2.11, P < 0.001; disease free survival: HR=1.28, 95% CI=0.60-1.96, P < 0.001]. The results of this meta-analysis indicate that decreased 5-hmC levels are an indicator of poor survival of cancer patients. Given variability related to ethnicity, cancer types and detection methods, additional well-designed studies with larger sample sizes are required to further confirm our findings.
Topics: 5-Methylcytosine; Cytosine; DNA Methylation; Humans; Lymphatic Metastasis; Neoplasms; Prognosis
PubMed: 27911867
DOI: 10.18632/oncotarget.13719 -
Frontiers in Cardiovascular Medicine 2022Endothelial-mesenchymal transition (EndMT) is a differentiation process in which endothelial cells lose their own characteristics and acquire mesenchymal-like...
Endothelial-mesenchymal transition (EndMT) is a differentiation process in which endothelial cells lose their own characteristics and acquire mesenchymal-like characteristics, which contributes to the formation and development of atherosclerotic plaques. Until now, there is still a lack of effective measures to treat atherosclerosis (AS), so there is an urgent need to understand the underlying mechanisms of AS. In addition, although various studies have shown that EndMT is involved in the pathological stages of cardiovascular diseases, such as myocardial fibrosis, myocardial hypertrophy, and hypertension, the specific molecular mechanisms driving EndMT are still in the exploratory stage. In this review, we review the role of histone modifications (methylation, demethylation and acetylation, deacetylation) on EndMT in cardiovascular disease, aiming to target histone-modifying enzymes to guide cardiovascular disease therapy.
PubMed: 36568553
DOI: 10.3389/fcvm.2022.1022988 -
Cancers Oct 2021The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side... (Review)
Review
The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and discusses results of clinical trials evaluating epigenetic interventions in past and ongoing clinical trials as monotherapy or combination therapy with either chemotherapy, radiotherapy or immunotherapy. Understanding the function of epigenetic modifiers in both preclinical and clinical settings will provide insight into a more rational design of clinical trials using epigenetic interventions and the patient subgroups that may benefit from such interventions.
PubMed: 34680389
DOI: 10.3390/cancers13205241 -
Galen Medical Journal 2019Methylenetetrahydrofolate reductase () is an enzyme that plays a crucial role as a methyl-group donor in demethylation of homocysteine. The aim of this systematic review... (Review)
Review
Methylenetetrahydrofolate reductase () is an enzyme that plays a crucial role as a methyl-group donor in demethylation of homocysteine. The aim of this systematic review and meta-analysis was to study the relationship between gene polymorphism and metabolic syndrome (MS). We used search engines and databases such as Science Direct, Google Scholar, Embase, Cochrane Library, and PubMed to identify eligible studies up to 2018. The articles were studied based on keywords including , mutation, variant, and polymorphism in combination with MS. Data was analyzed using Comprehensive Meta-Analysis version 2.2.064 software. After extracting the data from seven articles, the total number of subjects was 1280 in the patient group and 1374 in the control group. The odds ratio was estimated to be 1.078 for the allele model of T vs. C (95% confidence interval [CI]: 1.626-0.715), 1.157 for the allele model of CC vs. CT (95% CI: 0.829-1.615), 1.020 for the allele model of CT + TT vs. CC (95% CI: 1.611-0.646) and 0.799 for the allele model of TT vs. CC + CT (95% CI: 1.185- 0.539). As well, the results showed no statistically significant correlation between polymorphism genotypes of the gene and MS (P<0.05). In general, this study showed that the presence of C677T polymorphism in the gene has no effect on the incidence of MS.
PubMed: 34466514
DOI: 10.31661/gmj.v8i0.1472 -
International Journal of Molecular... Jan 2022Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that have become fixed in the human genome. While HERV genes are typically silenced...
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that have become fixed in the human genome. While HERV genes are typically silenced in healthy somatic cells, there are numerous reports of HERV transcription and translation across a wide spectrum of cancers, while T and B cell responses against HERV proteins have been detected in cancer patients. This review systematically categorizes the published evidence on the expression of and adaptive immune response against specific HERVs in distinct cancer types. A systematic literature search was performed using Medical Search Headings (MeSH) in the PubMed/Medline database. Papers were included if they described the translational activity of HERVs. We present multiple tables that pair the protein expression of specific HERVs and cancer types with information on the quality of the evidence. We find that HERV-K is the most investigated HERV. HERV-W (syncytin-1) is the second-most investigated, while other HERVs have received less attention. From a therapeutic perspective, HERV-K and HERV-E are the only HERVs with experimental demonstration of effective targeted therapies, but unspecific approaches using antiviral and demethylating agents in combination with chemo- and immunotherapies have also been investigated.
Topics: Animals; Antibody Formation; Endogenous Retroviruses; Host-Pathogen Interactions; Humans; Neoplasms; Retroviridae Infections; Viral Proteins
PubMed: 35163254
DOI: 10.3390/ijms23031330 -
Frontiers in Pharmacology 2020Epimutations secondary to gene-environment interactions have a key role in the pathophysiology of major psychiatric disorders. and evidence suggest that mood...
BACKGROUND
Epimutations secondary to gene-environment interactions have a key role in the pathophysiology of major psychiatric disorders. and evidence suggest that mood stabilizers can potentially reverse epigenetic deregulations found in patients with schizophrenia or mood disorders through mechanisms that are not yet fully understood. However, their activity on epigenetic processes has made them a research target for therapeutic approaches.
METHODS
We conducted a comprehensive literature search of PubMed and EMBASE for studies investigating the specific epigenetic changes induced by non-antipsychotic mood stabilizers (valproate, lithium, lamotrigine, and carbamazepine) in animal models, human cell lines, or patients with schizophrenia, bipolar disorder, or major depressive disorder. Each paper was reviewed for the nature of research, the species and tissue examined, sample size, mood stabilizer, targeted gene, epigenetic changes found, and associated psychiatric disorder. Every article was appraised for quality using a modified published process and those who met a quality score of moderate or high were included.
RESULTS
A total of 2,429 records were identified; 1,956 records remained after duplicates were removed and were screened title, abstract and keywords; 129 records were selected for full-text screening and a remaining of 38 articles were included in the qualitative synthesis. Valproate and lithium were found to induce broader epigenetic changes through different mechanisms, mainly DNA demethylation and histones acetylation. There was less literature and hence smaller effects attributable to lamotrigine and carbamazepine could be associated overall with the small number of studies on these agents. Findings were congruent across sample types.
CONCLUSIONS
An advanced understanding of the specific epigenetic changes induced by classic mood stabilizers in patients with major psychiatric disorders will facilitate personalized interventions. Further related drug discovery should target the induction of selective chromatin remodeling and gene-specific expression effects.
PubMed: 32390836
DOI: 10.3389/fphar.2020.00467