DNA Methyltransferases and Gastric Cancer: Insight Into Targeted Therapy

Fattahi, Sadegh; Golpour, Monireh; Amjadi‐Moheb, Fatemeh; Sharifi-Pasandi, Marzieh; Khodadadi, Parastesh; Pilehchian-Langroudi, Maryam; Ashrafi, G. Hossein; Akhavan‐Niaki, Haleh

doi:10.2217/epi-2018-0096

Cited by 25 publications

(24 citation statements)

References 187 publications

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“…DNA methylation is catalyzed by three DNMTs, DNMT1, DNMT3A, and DNMT3B, which all add a methyl group to the C5 position of the cytosine ring of the DNA to produce 5-methylcytosine (5-mC). DNMT1 mediates maintenance DNA methylation, whereas DNMT3a and 3b mediate de novo DNA methylation 24 . This methylation process is reversible by DNA demethylases, TET1, TET2, and TET3.…”

Section: Resultsmentioning

confidence: 99%

Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells

et al. 2019

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Luteolin, a dietary flavone, modulates various signaling pathways involved in carcinogenesis. In this study, we investigated the molecular mechanism that underlies the apoptotic effects of luteolin mediated by DNA demethylation of the nuclear factor erythroid 2-related factor 2 (Nrf2) promoter and the interaction of Nrf2 and p53, a tumor suppressor, in human colon cancer cells. Luteolin increased the expression of apoptosis-related proteins and antioxidant enzymes. In DNA methylation, luteolin inhibited the expression of DNA methyltransferases, a transcription repressor, and increased the expression and activity of ten-eleven translocation (TET) DNA demethylases, a transcription activator. Methyl-specific polymerase chain reaction and bisulfite genomic sequencing indicated that luteolin decreased the methylation of the Nrf2 promoter region, which corresponded to the increased mRNA expression of Nrf2. In addition, luteolin increased TET1 binding to the Nrf2 promoter, as determined using a chromatin immunoprecipitation (ChIP) assay. TET1 knockdown decreased the percentages of luteolin-treated cells in sub-G 1 phase and cells with fragmented nuclei. Furthermore, complex formation between p53 and Nrf2 was involved in the apoptotic effects of luteolin. These results provide insight into the mechanism that underlies the anticancer effects of luteolin on colon cancer, which involve the upregulation of Nrf2 and its interaction with the tumor suppressor.

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Section: Resultsmentioning

confidence: 99%

Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells

et al. 2019

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“…GC is one of the most common malignancies, causing one of the highest public health burdens[ 1 , 20 ]. Studies have shown that GC carcinogenesis is a multistep and multifactorial process caused by genetic changes and epigenetic alterations[ 2 , 21 ]. GC is characterized by accumulated genomic modifications, including somatic mutations and genomic amplifications and deletions[ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…GC is characterized by accumulated genomic modifications, including somatic mutations and genomic amplifications and deletions[ 22 ]. However, evidence has shown that both genomic aberrations and Helicobacter pylori -induced precursors are associated with multiple epigenetic changes, such as hypermethylation of tumor suppressors and hypomethylation of oncogenes[ 12 , 21 ]. For instance, Helicobacter pylori can induce methylation of multiple CpG islands in GC patients, which subsequently increases genome instability by stimulating activation-induced cytidine deaminase or altering microRNA expression[ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Signature based on molecular subtypes of deoxyribonucleic acid methylation predicts overall survival in gastric cancer

Bian¹,

Long²,

Xu³

et al. 2020

WJG

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BACKGROUND Gastric cancer (GC) ranks as the third leading cause of cancer-related death worldwide. Epigenetic alterations contribute to tumor heterogeneity in early stages. AIM To identify the specific deoxyribonucleic acid (DNA) methylation sites that influence the prognosis of GC patients and explore the prognostic value of a model based on subtypes of DNA methylation. METHODS Patients were randomly classified into training and test sets. Prognostic DNA methylation sites were identified by integrating DNA methylation profiles and clinical data from The Cancer Genome Atlas GC cohort. In the training set, unsupervised consensus clustering was performed to identify distinct subgroups based on methylation status. A risk score model was built based on Kaplan-Meier, least absolute shrinkage and selector operation, and multivariate Cox regression analyses. A test set was used to validate this model. RESULTS Three subgroups based on DNA methylation profiles in the training set were identified using 1061 methylation sites that were significantly associated with survival. These methylation subtypes reflected differences in T, N, and M category, age, stage, and prognosis. Forty-one methylation sites were screened as specific hyper- or hypomethylation sites for each specific subgroup. Enrichment analysis revealed that they were mainly involved in pathways related to carcinogenesis, tumor growth, and progression. Finally, two methylation sites were chosen to generate a prognostic model. The high-risk group showed a markedly poor prognosis compared to the low-risk group in both the training [hazard ratio (HR) = 2.24, 95% confidence interval (CI): 1.28-3.92, P < 0.001] and test (HR = 2.12, 95%CI: 1.19-3.78, P = 0.002) datasets. CONCLUSION DNA methylation-based classification reflects the epigenetic heterogeneity of GC and may contribute to predicting prognosis and offer novel insights for individualized treatment of patients with GC.

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“…In this direction, further studies are needed to better understand the interaction of epigenetic treatments and radiation therapy, given that these interesting results seem to be cell-type associated. Thus, despite the described side effects of epigenetic agents [ 140 ], the combination of these with chemo- and radiotherapy is a promising strategy and a hot topic for GC treatment, to maximize the potential of cytotoxic agents and radiation therapy. In recent years, non-nucleoside epigenetic compounds are attracting growing interest, because of their lower toxicity and the ability to bind and inhibit the catalytic domain of DNMTs, without integrating in DNA, and thus avoiding the non-specific effects of nucleoside analogues [ 102 ].…”

Section: Current and New Epigenetic Strategies For Gastric Cancer mentioning

confidence: 99%

Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities

Canale

Casadei-Gardini

Ulivi

et al. 2020

IJMS

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Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.

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DNA Methyltransferases and Gastric Cancer: Insight Into Targeted Therapy

Cited by 25 publications

References 187 publications

Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells

Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells

Signature based on molecular subtypes of deoxyribonucleic acid methylation predicts overall survival in gastric cancer

Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities

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