Fusaric acid-induced promoter methylation of DNA methyltransferases triggers DNA hypomethylation in human hepatocellular carcinoma (HepG2) cells

Ghazi, Terisha; Nagiah, Savania; Naidoo, Pragalathan; Chuturgoon, Anil A.

doi:10.1080/15592294.2019.1615358

Cited by 13 publications

(8 citation statements)

References 62 publications

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“…Then, the immuno-precipitates were recovered by centrifugation (2,500 g , 4°C, 60 s), washed three times in RNA immunoprecipitation buffer, followed by re-suspension in Qiazol Reagent (500 µl). RNA was isolated from both the reference and m6A-precipitated samples, as previously described [ 24 ]. The expression of p75NTR in the m6A-precipitated sample was normalized against the expression of p75NTR in the reference sample in order to determine the ratio of m6A methylated p75NTR relative to the total p75NTR expressed [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Ibuprofen promotes p75 neurotrophin receptor expression through modifying promoter methylation and N6-methyladenosine-RNA-methylation in human gastric cancer cells

Jiang

Tan

et al. 2022

Bioengineered

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It is acknowledged that nonsteroidal anti-inflammatory drugs (NSAIDs) can participate in various signaling pathways, while information about their epigenetic effects are limited. p75NTR (p75 neurotrophin receptor) can inhibit tumor growth by inducing cell cycle arrest and regulating cell cycle arrest and apoptotic cell death. The expression of p75NTR is influenced by epigenetic roles. We explored the effects of ibuprofen on p75NTR expression and investigated whether promoter methylation and N6-methyladenosine (m6A) RNA methylation regulates this process in human gastric cancer cells (SGC7901 and MKN45). Cell lines were treated with ibuprofen 0, 2.5, 5, 10, 20 µM, and then DNA, RNA, and protein were isolated 24 h later. Expression and promoter methylation of p75NTR were detected by RT-qPCR and Western blot. The levels of m6A-p75NTR were measured by RNA immunoprecipitation. We also used RT-qPCR to determine the levels of m6A-related regulators, METTL3, METTL14, ALKBH5, FTO, YTHDC2, and YTHDF1-3. Ibuprofen attenuated p75NTR promoter methylation ( p < 0.01) and increased p75NTR level ( p < 0.001). Ibuprofen increased m6A-p53 expression ( p < 0.01) by promoting the expression of METTL3 ( p < 0.01) and METTL14 ( p < 0.05); and increased levels of YTHDF1 ( p < 0.001), YTHDF3 ( p < 0.001), and YTHDC2 ( p < 0.01) that finally reinforced p53 translation ( p < 0.01). Therefore, our results present that ibuprofen epigenetically increased p75NTR expression by downregulating promoter methylation and upregulating m6A-RNA-methylation in SGC7901 and MKN45 cells. Our study unveils a novel mechanism for p75NTR regulation by NSAIDs and helps the design of treatment targets.

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Section: Methodsmentioning

confidence: 99%

Ibuprofen promotes p75 neurotrophin receptor expression through modifying promoter methylation and N6-methyladenosine-RNA-methylation in human gastric cancer cells

Jiang

Tan

et al. 2022

Bioengineered

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“…The average methylation status of the above 15 CG pairs was notably exceeded in the peripheral CD4 + T cells in RA patients than that found in the health individuals (Figure 6C). It is well known that DNA methylation is regulated by DNA methyltransferases (DNMTs) (20,21). We then examined expression of DNMTs on CD4 + T cells and found that among DNMT1, DNMT3A, and DNMT3B, only DNMT1 mRNA expression was negatively correlated with the expression of Smad7 in CD4 + T cells (Figures 6D-F).…”

Section: Loss Of Smad7 Is Associated With Hypermethylation Of Smad7 P...mentioning

confidence: 95%

Hypermethylation of Smad7 in CD4+ T cells is associated with the disease activity of rheumatoid arthritis

et al. 2023

Front. Immunol.

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BackgroundSmad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whether Smad7-expressing CD4+ T cells and the methylation of Smad7 gene in CD4+ T cells contribute to the disease activity of RA in patients.MethodsPeripheral CD4+ T cells were collected from 35 healthy controls and 57 RA patients. Smad7 expression by CD4+ T cells were determined and correlated with the clinical parameters of RA including RA score and serum levels of IL-6, CRP, ESR, DAS28-CRP, DAS28-ESR, Swollen joints and Tender joints. Bisulfite sequencing (BSP-seq) was used to determine the DNA methylation in Smad7 promoter (-1000 to +2000) region in CD4+ T cells. In addition, a DNA methylation inhibitor, 5-Azacytidine (5-AzaC), was added to CD4+ T cells to examine the possible role of Smad7 methylation in CD4+ T cell differentiation and functional activity.ResultsCompared to the heath controls, Smad7 expression was significantly decreased in CD4+ T cells from RA patients and inversely correlated with the RA activity score and serum levels of IL-6 and CRP. Importantly, loss of Smad7 in CD4+ T cell was associated with the alteration of Th17/Treg balance by increasing Th17 over the Treg population. BSP-seq detected that DNA hypermethylation occurred in the Smad7 promoter region of CD4+ T cells obtained from RA patients. Mechanistically, we found that the DNA hypermethylation in the Smad7 promoter of CD4+ T cells was associated with decreased Smad7 expression in RA patients. This was associated with overreactive DNA methyltransferase (DMNT1) and downregulation of the methyl-CpG binding domain proteins (MBD4). Inhibition of DNA methylation by treating CD4+ T cells from RA patients with 5-AzaC significantly increased Smad7 mRNA expression along with the increased MBD4 but reduced DNMT1 expression, which was associated with the rebalance in the Th17/Treg response.ConclusionDNA hypermethylation at the Smad7 promoter regions may cause a loss of Smad7 in CD4+ T cells of RA patients, which may contribute to the RA activity by disrupting the Th17/Treg balance.

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“…Some of the main food-borne mycotoxins—fusaric acid, fumonisin B 1 , deoxynivalenol, T-2 toxin, zearalenone, ochratoxin A, and aflatoxin B 1 ( Figure 4 )—have been shown to induce a change in the DNA methylation profile in human cell lines and animal models [ 213 , 214 , 215 , 216 , 217 , 218 , 219 ].…”

Section: Mycotoxinsmentioning

confidence: 99%

“…This study indicated that FA decreased 5-methylcytosine DNA content, which is indicative of global DNA hypomethylation in the HepG2 cell line. The decrease in global DNA methylation occurred as a result of the decrease in DNMT1, DNMT3A, and DNMT3B expression as well as an increase in MBD2 expression [ 213 ]. Furthermore, FA was shown to decrease DNMT1, DNMT3A, and DNMT3B expressions by inducing promoter hypermethylation of the DNMTs .…”

Section: Mycotoxinsmentioning

confidence: 99%

“…Furthermore, FA was shown to decrease DNMT1, DNMT3A, and DNMT3B expressions by inducing promoter hypermethylation of the DNMTs . Similarly, the FA-induced increase in MBD2 expression was shown to occur due to MBD2 promoter hypomethylation [ 213 ]. This study indicated that FA may induce genotoxicity and cytotoxicity in the HepG2 cell line by altering their DNA methylation profile.…”

Section: Mycotoxinsmentioning

confidence: 99%

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The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

Ghazi

Arumugam

Foolchand

et al. 2020

Cells

Self Cite

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Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.

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Fusaric acid-induced promoter methylation of DNA methyltransferases triggers DNA hypomethylation in human hepatocellular carcinoma (HepG2) cells

Cited by 13 publications

References 62 publications

Ibuprofen promotes p75 neurotrophin receptor expression through modifying promoter methylation and N6-methyladenosine-RNA-methylation in human gastric cancer cells

Ibuprofen promotes p75 neurotrophin receptor expression through modifying promoter methylation and N6-methyladenosine-RNA-methylation in human gastric cancer cells

Hypermethylation of Smad7 in CD4+ T cells is associated with the disease activity of rheumatoid arthritis

The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

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