• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4539-4543
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• 2014

Since the epigenetic alteration in tumor cells can be reversed by the dietary polyphenol quercetin (Q) or butyrate (B) with chemopreventive activity, suggesting that Q or B can be used for chemopreventive as well as therapeutic agent against tumors. In this study the polyphenol flavonoid quercetin (Q) or sodium butyrate (B) suppressed human esophageal 9706 cancer cell growth in dose dependent manner, and Q combined with B (Q+B) could further inhibit Eca9706 cell proliferation than that induced by Q or B alone, compared with untreated control group (C) in MTT assay. The reverse expressions of global DNMT1, $NF-{\kappa}Bp65$, HDAC1 and Cyclin D1 were down-regulated, while expressions of caspase-3 and $p16INK4{\alpha}$ were up-regulated, compared with the C group in immunoblotting; the down-regulated HDAC1-IR (-immunoreactivity) with nuclear translocation, and up-regulated E-cadherin-IR demonstrated in immunocytochemistry treated by Q or B, and Q+B also displayed further negatively and positively modulated effects compared with C group. The order of methylation specific (MS) PCR of $p16INK4{\alpha}$: C>B/Q>Q+B group, while the order of E-cadherin expression level was contrary, Q+B>Q/B>C group. Thus, Q/B, especially Q+B display reverse effect targeting both altered DNA methylation and histone acetylation, acting as histone deacetylase inhibitor mediated via epigenetic-$NF-{\kappa}B$ cascade signaling.

• YAKHAK HOEJI
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• v.49 no.6
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• pp.511-517
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• 2005

Low sensitivity to anticancer drugs such as 5-fluorouracil (5-FU) has been associated with decreased expression of genes involved in cell proliferation, apoptosis and metastasis. Recently, it has been shown that the expression levels of some of these genes are reduced by transcription inhibition due to epigenetic silencing on CpG islands. Therefore, epigenetic therapy has been proposed, where epigenetic silencing is repressed with DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors alone or in combination with other chemotherapeutic agents. The aim of our study was to evaluate the combination effect of 5-FU and its association with the status of epigenetic silencing using methylation-specific PCR of $p14^{ARF}$ when given with S-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor and depsipeptide, an HDAC inhibitor in DLD-1 human colorectal cancer cells. The combination of 5-aza-dC with depsipeptide showed a synergism and induced unmethylation of $p14^{ARF}$. However, triplet combination of 5-aza-dc/depsipeptide and 5-FU resulted in antagonistic effects and abrogated unmethylation of $p14^{ARF}$. These results suggest that unfavorable interaction of 5-aza-dC/depsipeptide with 5-FU in DLD-1 cells may be related with the failure in repression of epigenetic silencing, which warrants further investigation.

• Journal of Life Science
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• v.33 no.9
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• pp.730-735
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• 2023

In the past decade, numerous studies have been carried out to quantify aging with the help of artificial intelligence. Using DNA methylation data, various models have been developed; these are commonly called epigenetic clocks. Epigenetic age acceleration is usually associated with disease conditions. Schizophrenia is a mental illness associated with severe mental and physical stress. This disease leads to high mortality and morbidity rates in young people compared with other psychological disorders. In the past, the research community considered this disease to be related to the accelerated aging hypothesis. In the current study, we wanted to investigate the epigenetic age acceleration changes in schizophrenia patients to obtain epigenetic insights into the disease. To measure the epigenetic age acceleration, we used two different DNA methylation clock models, namely, Horvath clock and Epi clock, as these are pan-tissue models. We utilized 450k array data compatible with both clocks. We found a slower epigenetic acceleration in the patients' samples when we used the Epi clock. We further analyzed the differentially methylated CpG sites between the control and cases and performed pathway enrichment analysis. We found that most of the CpGs are involved in neuronal processes.

• Journal of Life Science
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• v.34 no.7
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• pp.520-530
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• 2024

Tumor suppressor genes (TSGs) play a crucial role in maintaining cellular homeostasis. When the function of these genes is lost, it can lead to cellular plasticity that drives the development of various cancers, including small-cell lung cancer (SCLC), which is known for its aggressive nature. SCLC is primarily driven by numerous loss-of-function mutations in TSGs, often involving genes that encode epigenetic regulators. These mutations pose a significant therapeutic challenge as they are not directly targetable. However, understanding the molecular changes resulting from these mutations might provide insights for developing tumor intervention strategies. We propose that despite the heterogeneous genomic landscape of SCLC, the effects of mutations in patient tumors converge on a few critical pathways that drive malignancy. Specifically, alterations in epigenetic regulators lead to transcriptional dysregulation, pushing mutant cells toward a highly plastic state that makes them immune evasive and highly metastatic. This review will highlight studies showing how an imbalance of epigenetic regulators with opposing functions leads to the loss of immune recognition markers, effectively hiding tumor cells from the immune system. Additionally, we will discuss the role of epigenetic regulators in maintaining neuroendocrine features and how aberrant transcriptional control promotes epithelial-to-mesenchymal transition during tumor development. Although these pathways seem distinct, we emphasize that they often share common molecular drivers and mediators. Understanding the connection among frequently altered epigenetic regulators will provide valuable insights into the molecular mechanisms underlying SCLC development, potentially revealing preventive and therapeutic vulnerabilities for SCLC and other cancers with similar mutations.

• BMB Reports
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• v.40 no.2
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• pp.142-150
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• 2007

Epigenetic alterations, represented by aberrant DNA methylation, are deeply involved in human cancers. In gastric cancers, tumor-suppressor genes are inactivated more frequently by promoter methylation than by mutations. We recently showed that H. pylori infection, a potent gastric carcinogenic factor, induces methylation of specific genes in the gastric mucosae. When the methylation levels were analyzed in the gastric mucosae of healthy volunteers, cases with a single gastric cancer, and cases with multiple gastric cancers, who have increasing levels of risks for gastric cancers, there was a significant increasing trend in the methylation levels among the individuals without current H. pylori infection. This finding unequivocally showed the presence of an epigenetic field for cancerization. The degree of the field defect was measured more conveniently using methylation levels of marker genes than using those of tumor-suppressor genes. The presence of an epigenetic field for cancerization has been indicated for liver, colon, Barrett's esophageal, lung, breast, and renal cancers. Since decreased transcription is involved in the specificity of methylated genes, it is likely that specific genes are methylated according to carcinogenic factors. These findings emphasize the usefulness of DNA methylation as a marker for past exposure to carcinogens and future risk of cancer development.

• Journal of Environmental Health Sciences
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• v.35 no.5
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• pp.343-354
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• 2009

Since Barker found associations between low birth weight and several chronic diseases later in life, the hypothesis of fetal origins of adult disease (aka, Barker Hypothesis) and epigenetics have been emerging as a new paradigm for geneenvironment interaction of chronic disease. Epigenetics is the study of heritable changes in gene silencing that occur without any change in DNA sequence. Gene expression can be regulated by several epigenetic mechanisms, including DNA methylation and histone modifications, which may be associated with chronic conditions, such as cancers, cardiovascular disease, and type-2 diabetes. One carbon metabolism which involves the transfer of a methyl group catalyzed by DNA methyltransferase is an important mechanism by which DNA methylation occurs in promoter regions and/or repetitive elements of the genome. Environmental factors may induce epigenetic modification through production of reactive oxygen species, alteration of methyltransferase activity, and/or interference with methyl donors. In this review, we introduce recent studies of epigenetic modification and environmental factors, such as heavy metals, environmental hormones, air pollution, diet and psychosocial stress. We also discuss epigenetic perspectives of early life environmental exposure and late life disease occurrence.

• Journal of Microbiology and Biotechnology
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• v.27 no.8
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• pp.1367-1378
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• 2017

Epigenetic alterations such as DNA methylation, histone acetylation, and chromatin remodeling can control gene expression by regulating gene transcription. DNA methylation is one of the frequent epigenetic events that play important roles in cancer development. Cancer cells can gain significant resistance to anticancer drugs and escape programmed cell death through major epigenetic changes, including DNA methylation. To date, several research groups have identified instances of both (i) hypermethylation of tumor suppressor genes, and (ii) global hypomethylation of oncogenes. These changes in DNA methylation status could be used as biomarkers for the diagnosis and prognosis of cancer patients undergoing chemotherapies or other clinical therapies. Herein, we describe genes for which methylation is dependent upon anticancer drug resistance in patients with gastric cancer; we then suggest a significant epigenetic target to focus on for overcoming anticancer drug resistance.

• Journal of Integrative Natural Science
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• v.16 no.2
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• pp.61-67
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• 2023

Human body ages differently due to environmental, genetic and pathological factors. DNA methylation patterns also differs depending on various factors such as aging and several other diseases. The aging clock model, which uses these differences to predict age, analyzes DNA methylation patterns, recognizes age-specific patterns, predicts age, and grasps the speed and degree of aging. Aging occurs in everyone and causes various problems such as deterioration of physical ability and complications. Alzheimer's disease is a disease associated with aging and the most common brain degenerative disease. This disease causes various cognitive functions disabilities such as dementia and impaired judgment to motor functions, making daily life impossible. It has been reported that the incidence and progression of this disease increase with aging, and that increased phosphorylation of Aβ and tau proteins, which are overexpressed in this disease and accelerates epigenetic aging. It has also been reported that DNA methylation is significantly increased in the hippocampus and entorhinal cortex of Alzheimer's disease patients. Therefore, we calculated the biological age using the Epi clock, a pan-tissue aging clock model, and confirmed that the epigenetic age of patients suffering from Alzheimer's disease is lower than their actual age. Also, it was confirmed to slow down aging.

• Journal of Integrative Natural Science
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• v.16 no.3
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• pp.75-80
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• 2023

Bipolar disorder is a mental illness characterized by extreme mood and behavioral swings, such as highs of euphoria and lows of depression. It is a socially significant disorder in which people with the disorder experience intense mood swings and, for those with severe bipolar disorder, it is even difficult leading a normal life. High stress levels in people with mental illness can lead to neuroendocrine disruption, and it is strongly linked to aging. When the neuroendocrine system becomes vulnerable to these mental illnesses and stress, it is likely to accelerate aging. And it's the epigenetic clock that can measure the extent of this accelerated aging. The Epi clock, a pan tissue clock, measures aging through DNA methylation, and the degree of methylation is modified and changed by environmental conditions in the body. Therefore we wanted to check the changes in the epigenetic age of the patients with bipolar disorder. While we found no significant differences in epigenetic age, we did confirm the possibility that people with bipolar disorder have different methylation than normal people. We also found that the EPIC array data fit better on the Epi clock than on the Horvath clock with age-accelerated data from normal people.

• IMMUNE NETWORK
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• v.23 no.1
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• pp.5.1-5.28
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• 2023

Th cell lineage determination and functional specialization are tightly linked to the activation of lineage-determining transcription factors (TFs) that bind cis-regulatory elements. These lineage-determining TFs act in concert with multiple layers of transcriptional regulators to alter the epigenetic landscape, including DNA methylation, histone modification and threedimensional chromosome architecture, in order to facilitate the specific Th gene expression programs that allow for phenotypic diversification. Accumulating evidence indicates that Th cell differentiation is not as rigid as classically held; rather, extensive phenotypic plasticity is an inherent feature of T cell lineages. Recent studies have begun to uncover the epigenetic programs that mechanistically govern T cell subset specification and immunological memory. Advances in next generation sequencing technologies have allowed global transcriptomic and epigenomic interrogation of CD4+ Th cells that extends previous findings focusing on individual loci. In this review, we provide an overview of recent genome-wide insights into the transcriptional and epigenetic regulation of CD4+ T cell-mediated adaptive immunity and discuss the implications for disease as well as immunotherapies.