The impact of polyunsaturated fatty acids on DNA methylation and expression of DNMTs in human colorectal cancer cells

Sarabi, Mostafa Moradi; Naghibalhossaini, Fakhraddin

doi:10.1016/j.biopha.2018.02.077

Cited by 24 publications

(26 citation statements)

References 40 publications

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“…Our results show that the five CRC cell lines probably reflect differences in miR-126 promoter methylation in response to PUFA treatment. The demethylating effect of DHA observed by us in Caco2 cells confirms the finding of our previous study obtained in the same colorectal cancer cells [34]. The rationale for using 100 μM concentration as the selected dose was that it is below or within the reported circulating fatty acid range [42].…”

Section: Discussionsupporting

confidence: 84%

“…We have found previously that the HCT116 and Caco2 cells significantly expressed high levels of DNMTs compared to other CRC cell lines [54]. Moreover, we previously verified that n -3 and n -6 PUFAs significantly downregulated DNMTs in HCT116 and Caco2 cells [34]. Both EPA and DHA reduce VEGF protein expression level in HCT116 cells, but they do not show similar effectiveness, with DHA being much more efficient than EPA and LA not only in reducing the promoter methylation of miR-126 but also in increasing level of miR-126 and decreasing level of VEGF protein expression in both HCT116 and Caco2 cell lines.…”

Section: Discussionmentioning

confidence: 72%

“…Many studies have indicated that n -3 PUFAs inhibited tumor growth by preventing the decrease in genomic DNA methylation in the CRC rat models [13]. Moreover, our quite recent study indicated that PUFAs altered the global and cell-type specific DNA methylation in human CRC cells [34]. However, the precise mechanism by which dietary PUFAs mediate epigenetic modifications in human cells is not fully demonstrated, and to our best knowledge in scientific literature, no published studies have yet examined if PUFAs can directly affect the alteration promoter methylation of miRNAs.…”

Section: Introductionmentioning

confidence: 99%

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The effects of dietary polyunsaturated fatty acids on miR-126 promoter DNA methylation status and VEGF protein expression in the colorectal cancer cells

et al. 2018

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BackgroundThere is increasing evidence indicating an aberrant expression of miRNAs in colorectal cancer (CRC) development. Growing evidence has suggested that polyunsaturated fatty acids (PUFAs) could modulate the remodeling of the epigenome. No study has yet been published to examine the direct effect of PUFA on the promoter methylation of miRNAs. This study aimed to examine the potential clinical application of PUFA on the promoter DNA methylation of miR-126 and its angiogenic target molecule (VEGF) in the CRC cells.MethodsWe investigated the direct effect of 100 μM EPA, DHA, and LA for 24 h on promoter methylation status of miR-126 in a panel of five CRC cell lines (HCT116, HT29/219, Caco2, SW742, and LS180) by methylation-specific PCR (MSP). We also quantified the miR-126 and VEGF transcript expression levels in five CRC cell lines affected by PUFA by real-time PCR. Moreover, we analyzed the protein expression level of VEGF, as a target of miR-126, by western blotting assay.ResultsMSP analysis showed extensive DNA methylation of the miR-126 promoter in all five CRC cell lines, and among all three PUFAs, only DHA completely demethylated the promoter of miR-126 in HCT116 and Caco2 cell lines. We found that only DHA significantly induces the expression level of miR-126 in HCT116 and Caco2 cell lines, respectively, by 20.1-fold and 1.68-fold (p < 0.05). Our finding indicates that the downregulation of VEGF protein level is also effectively observed only in DHA-treated HCT116 and Caco2 cells compared to control cells (p < 0.05).ConclusionsOur results provide evidence that n-3 PUFAs are able to modulate cellular miR-126 DNA methylation and inhibit VEGF expression level in a cell-type specific manner in colorectal cancer cells. DHA always showed higher efficacy than EPA and LA in our experiment. Overall, our results suggest a potential clinical application of n-3 PUFAs as anti-angiogenic agents in CRC therapy.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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The effects of dietary polyunsaturated fatty acids on miR-126 promoter DNA methylation status and VEGF protein expression in the colorectal cancer cells

et al. 2018

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“…Genomic DNA was extracted from the HESC by the standard method of proteinase K digestion, phenolchloroform extraction and ethanol precipitation described previously [32].…”

Section: Genomic Dna Preparationmentioning

confidence: 99%

Nicotine attenuates global genomic DNA methylation by influencing DNMTs gene expression in human endometrial stromal cells

et al. 2020

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Background: There is increasing evidence indicating an incidence of infertility and also the risk of endometrial cancers among smokers. However, the mechanism underlying nicotine adverse effect on female reproduction remains unclear. Growing evidence has suggested that environmental exposures such as nicotine could modulate the epigenome. No study has yet been published to evaluate the direct effect of nicotine on the epigenome profiling of human endometrial stromal cells (HESC). Herein, we decided to examine the direct effects of nicotine on global genomic DNA methylation status and DNA methyl-transferases (DNMTs) gene expression in HESC. HESC were treated with different doses of nicotine (0 or control, 10 − 11 , 10 − 8 and 10 − 6) M for 24 h and their genomic global DNA methylation and gene expression of DNMTs (DNMT1, DNMT3A, and DNMT3B) were investigated using ELISA and real-time PCR, respectively. Results: Nicotine treatments reduced the average level of DNMTs gene expression by 90, 79, and 73.4% in 10 − 11 , 10 − 8 and 10 − 6 M of nicotine treated cells as compared to control cells, respectively (p < 0.05). Also, 10 − 8 and 10 − 6 M of nicotine concentrations effectively reduced the amounts of 5-methylated cytosine (5-mC) by 1.09 and 1.87% compared to control cells, respectively (p < 0.05). The 5-mC percentages were positively correlated with the relative cellular DNMTs expression in HESC as verified by the Pearson correlation test. Conclusion: An interesting possibility raised by the current study is that the reduced genomic global DNA methylation level in HESC may be partly due to the suppression of DNMTs gene expression caused by nicotine in these cells.

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“…Microsatellites or simple sequence repeats are tracts of 15-30 repeated DNA units composed of 1-6 nucleotides distributed among all DNA regions (coding and noncoding). Instability of microsatellites result from sporadic or germline mutations in DNA mismatch repair (MMR) machinery genes including PMS1 , PMS6 , MSH2 , MSH6 , MGMT and MLH1 , which are responsible for correcting errors occurring during DNA replication[ 36 - 38 ].…”

Section: Microsatellite Instability and Resistance To 5-fumentioning

confidence: 99%

Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids

Aghabozorgi

Sarabi

Koochakkhani

et al. 2020

WJGO

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5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.

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The impact of polyunsaturated fatty acids on DNA methylation and expression of DNMTs in human colorectal cancer cells

Cited by 24 publications

References 40 publications

The effects of dietary polyunsaturated fatty acids on miR-126 promoter DNA methylation status and VEGF protein expression in the colorectal cancer cells

The effects of dietary polyunsaturated fatty acids on miR-126 promoter DNA methylation status and VEGF protein expression in the colorectal cancer cells

Nicotine attenuates global genomic DNA methylation by influencing DNMTs gene expression in human endometrial stromal cells

Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids

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