• Toxicological Research
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• v.31 no.1
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• pp.1-9
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• 2015

Environmental toxicants such as toxic metals can alter epigenetic regulatory features such as DNA methylation, histone modification, and non-coding RNA expression. Heavy metals influence gene expression by epigenetic mechanisms and by directly binding to various metal response elements in the target gene promoters. Given the role of epigenetic alterations in regulating genes, there is potential for the integration of toxic metal-induced epigenetic alterations as informative factors in the risk assessment process. Here, we focus on recent advances in understanding epigenetic changes, gene expression, and biological effects induced by toxic metals.

• Biomolecules & Therapeutics
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• v.26 no.1
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• pp.69-80
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• 2018

Cancer cells reprogram cellular metabolism to support the malignant features of tumors, such as rapid growth and proliferation. The cancer promoting effects of metabolic reprogramming are found in many aspects: generating additional energy, providing more anabolic molecules for biosynthesis, and rebalancing cellular redox states in cancer cells. Metabolic pathways are considered the pipelines to supply metabolic cofactors of epigenetic modifiers. In this regard, cancer metabolism, whereby cellular metabolite levels are greatly altered compared to normal levels, is closely associated with cancer epigenetics, which is implicated in many stages of tumorigenesis. In this review, we provide an overview of cancer metabolism and its involvement in epigenetic modifications and suggest that the metabolic adaptation leading to epigenetic changes in cancer cells is an important non-genetic factor for tumor progression, which cooperates with genetic causes. Understanding the interaction of metabolic reprogramming with epigenetics in cancers may help to develop novel or highly improved therapeutic strategies that target cancer metabolism.

• 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.

• Biomolecules & Therapeutics
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• v.26 no.6
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• pp.591-598
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• 2018

Epigenetic silencing is considered to be a major mechanism for loss of activity in tumor suppressors. Reversal of epigenetic silencing by using inhibitors of DNA methyltransferase (DNMT) or histone deacetylases (HDACs) such as 5-Aza-CdR and FK228 has shown to enhance cytotoxic activities of several anticancer agents. This study aims to assess the combinatorial effects of genesilencing reversal agents (5-Aza-CdR and FK228) and oxaliplatin in gastric cancer cells, i.e., Epstein-Barr virus (EBV)-negative SNU-638 and EBV-positive SNU-719 cells. The doublet combinatorial treatment of 5-Aza-CdR and FK228 exhibited synergistic effects in both cell lines, and this was further corroborated by Zta expression induction in SNU-719 cells. Three drug combinations as 5-Aza-CdR/FK228 followed by oxaliplatin, however, resulted in antagonistic effects in both cell lines. Simultaneous treatment with FK228 and oxaliplatin induced synergistic and additive effects in SNU-638 and SNU-719 cells, respectively. Three drug combinations as 5-Aza-CdR prior to FK228/oxaliplatin, however, again resulted in antagonistic effects in both cell lines. This work demonstrated that efficacy of doublet synergistic combination using DNMT or HDACs inhibitors can be compromised by adding the third drug in pre- or post-treatment approach in gastric cancer cells. This implies that the development of clinical trial protocols for triplet combinations using gene-silencing reversal agents should be carefully evaluated in light of their potential antagonistic effects.

• Environmental Analysis Health and Toxicology
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• v.19 no.2
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• pp.119-134
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• 2004

Human exposure to highly nickel-polluted environments, such as those associated with nickel refining, electroplating, and welding, has the potential to produce a variety of pathologic effects. Among them are skin allergies, lung fibrosis, and cancer of the respiratory tract. The exact mechanisms of nickel-induced carcinogenesis are not known and have been the subject of numerous epidemiologic and experimental investigations. This review provides the evidence of the current state for the genotoxic and mutagenic activity of Ni (II) particularly at high doses. Such doses are best delivered into the cells by phagocytosis of sparingly soluble nickel-containing dust particles. Ni (II) genotoxicity may be aggravated through the generation of DNA-damaging reactive oxygen species (ROS) and the inhibition of DNA repair by this metal. The epigenetic effects of nickel includes alteration in gene expression resulting from DNA hypermethylation and histone hypoacetylation, as well as activation some signaling pathways and subsequent transcrziption factors.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6433-6438
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• 2013

In hepatocellular cancer (HCC), lack of response to chemotherapy and radiation treatment can be caused by a loss of epigenetic modifications of cancer cells. Methionine adenosyltransferase 1A is inactivated in HCC and may be stimulated by an epigenetic change involving promoter hypermethylation. Therefore, drugs releasing epigenetic repression have been proposed to reverse this process. We studied the effect of the demethylating reagent 5-aza-2'-deoxycitidine (5-Aza-CdR) on MAT1A gene expression, DNA methylation and S-adenosylmethionine (SAMe) production in the HCC cell line Huh7. We found that MAT1A mRNA and protein expression were activated in Huh7 cells with the treatment of 5-Aza-CdR; the status of promoter hypermethylation was reversed. At the same time, MAT2A mRNA and protein expression was significantly reduced in Huh7 cells treated with 5-Aza-CdR, while SAMe production was significantly induced. However, 5-Aza-CdR showed no effects on MAT2A methylation. Furthermore, 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis and through down-regulation of Bcl-2, up-regulation of Bax and caspase-3. Our observations suggest that 5-Aza-CdR exerts its anti-tumor effects in Huh7 cells through an epigenetic change involving increased expression of the methionine adenosyltransferase 1A gene and induction of S-adenosylmethionine production.

• Nutrition Research and Practice
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• v.17 no.1
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• pp.13-31
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• 2023

BACKGROUND/OBJECTIVES: Epigenetic regulation by nutrients can influence the development of specific diseases. This study sought to examine the effect of individual nutrients and nutrient families in the context of preventing chronic metabolic diseases via epigenetic regulation. The inhibition of lipid accumulation and inflammation by nutrients including proteins, lipids, vitamins, and minerals were observed, and histone acetylation by histone acetyltransferase (HAT) was measured. Correlative analyses were also performed. MATERIALS/METHODS: Nutrients were selected according to information from the Korean Ministry of Food and Drug Safety. Selected nutrient functionalities, including the attenuation of fatty acid-induced lipid accumulation and lipopolysaccharide-mediated acute inflammation were evaluated in mouse macrophage Raw264.7 and mouse hepatocyte AML-12 cells. Effects of the selected nutrients on in vitro HAT inhibition were also evaluated. RESULTS: Nitric oxide (NO) production correlated with HAT activity, which was regulated by the amino acids group, suggesting that amino acids potentially contribute to the attenuation of NO production via the inhibition of HAT activity. Unsaturated fatty acids tended to attenuate inflammation by inhibiting NO production, which may be attributable to the inhibition of in vitro HAT activity. In contrast to water-soluble vitamins, the lipid-soluble vitamins significantly decreased NO production. Water- and lipid-soluble vitamins both exhibited significant inhibitory activities against HAT. In addition, calcium and manganese significantly inhibited lipid accumulation, NO production, and HAT activity. CONCLUSIONS: Several candidate nutrients and their family members may have roles in the prevention of diseases, including hepatic steatosis and inflammation-related diseases (i.e., nonalcoholic steatohepatitis) via epigenetic regulation. Further studies are warranted to determine which specific amino acids, unsaturated fatty acids and lipid-soluble vitamins or specific minerals influence the development of steatosis and inflammatory-related diseases.

• 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.55 no.6
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• pp.287-292
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• 2022

The acute response to hypoxia is mainly driven by hypoxia-inducible factors, but their effects gradually subside with time. Hypoxia-specific histone modifications may be important for the stable maintenance of long-term adaptation to hypoxia. However, little is known about the molecular mechanisms underlying the dynamic alterations of histones under hypoxic conditions. We found that the phosphorylation of histone H3 at Ser-10 (H3S10) was noticeably attenuated after hypoxic challenge, which was mediated by the inhibition of aurora kinase B (AURKB). To understand the role of AURKB in epigenetic regulation, DNA microarray and transcription factor binding site analyses combined with proteomics analysis were performed. Under normoxia, phosphorylated AURKB, in concert with the repressor element-1 silencing transcription factor (REST), phosphorylates H3S10, which allows the AURKB-REST complex to access the MDM2 proto-oncogene. REST then acts as a transcriptional repressor of MDM2 and downregulates its expression. Under hypoxia, AURKB is dephosphorylated and the AURKB-REST complex fails to access MDM2, leading to the upregulation of its expression. In this study, we present a case of hypoxia-specific epigenetic regulation of the oxygen-sensitive AURKB signaling pathway. To better understand the cellular adaptation to hypoxia, it is worthwhile to further investigate the epigenetic regulation of genes under hypoxic conditions.