DNA methyltransferases: emerging targets for the discovery of inhibitors as potent anticancer drugs

Yu, Jie; Xie, Tianli; Wang, Zhe; Wang, Xuwen; Zeng, Su; Kang, Yu; Hou, Tingjun

doi:10.1016/j.drudis.2019.08.006

Cited by 51 publications

(44 citation statements)

References 67 publications

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“…DNA methylation causes changes in the chromatin structure, DNA conformation, DNA stability, and the proteins-DNA interaction, thereby regulating gene expression. In DNA methylation, a methyl group is covalently bound to the 5 carbon of cytosine, of the genomic CpG dinucleotide, under the catalysis of DNA methyltransferase (Yu et al, 2019). Here, we analyzed the correlation between gene expression and the expression of four methyltransferases (DNMT1, DNMT2, DNMT3A, and DNMT3B).…”

Section: Correlation Between Ace2 Expressionmentioning

confidence: 99%

Systematic Analysis of Coronavirus Disease 2019 (COVID-19) Receptor ACE2 in Malignant Tumors: Pan-Cancer Analysis

Song

Han

Liu

et al. 2020

Front. Mol. Biosci.

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Background: Coronavirus disease 2019 (COVID-19) was first detected in patients with pneumonia in December 2019 in China and it spread rapidly to the rest of the world becoming a global pandemic. Several observational studies have reported that cancer is a risk factor for COVID-19. On the other hand, ACE2, a receptor for the SARS-CoV-2 virus, was found to be aberrantly expressed in many tumors. However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated. Here, we conducted a systematic analysis of the ACE2 expression profile across 31 types of tumors. Methods: Distribution of ACE2 expression was analyzed using the GTEx, CCLE, TCGA pan-cancer databases. We evaluated the effect of ACE2 on clinical prognosis using the Kaplan-Meier survival plot and COX regression analysis. Correlation between ACE2 and immune infiltration levels was investigated in various cancer types. Additionally, the correlation between ACE2 and immune neoantigen, TMB, microsatellite instability, Mismatch Repair Genes (MMRs), HLA gene members, and DNA Methyltransferase (DNMT) was investigated. The frequency of ACE2 gene mutation in various tumors was analyzed. Functional enrichment analysis was conducted in various cancer types using the GSEA method. Results: In normal tissues, ACE2 was highly expressed in almost all 31 organs tested. In cancer cell lines, the expression level of ACE2 was low to medium. Although aberrant expression was observed in most cancer types, high expression of ACE2 was not linked to OS, DFS, RFS, and DFI in most tumors in TCGA pan-cancer data. We found that ACE2 expression was significantly correlated with the infiltrating levels of macrophages and dendritic cells, CD4+ T cells, CD8+ T cells, and B cells in multiple tumors. A positive correlation between ACE2 expression and immune neoantigen, TMB, and microsatellite instability was found in multiple cancers. GSEA analysis which was

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Section: Correlation Between Ace2 Expressionmentioning

confidence: 99%

Systematic Analysis of Coronavirus Disease 2019 (COVID-19) Receptor ACE2 in Malignant Tumors: Pan-Cancer Analysis

Song

Han

Liu

et al. 2020

Front. Mol. Biosci.

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“…. At the same time, S-nicotine is suggested to be metabolized into nicotine imine by the enzymatic action of cytochrome P450 family of enzymes (Nwosu et al, 1988;Berkman et al, 1995;von Weymarn et al, 2002;Kilgore et al, 2013;Jeltsch et al, 2016;Miletić et al, 2017;Yu et al, 2019). These data support the idea of existence of metabolic-epigenesis in cancer cells that supports growth and proliferation.…”

Section: Sam Dna Methylation and Cancermentioning

confidence: 77%

“…Additionally, the use of SAM is indicated in the formation of N-methylnicotinium ion from the R-nicotine by an unknown class of methyltransferases in case of cancer cells(Nwosu et al, 1988;Berkman et al, 1995; von Weymarn et al, 2002;Kilgore et al, 2013; Jeltsch et al., 2016; Miletić et al, 2017;Yu et al, 2019)…”

mentioning

confidence: 99%

Detection of oncometabolites 1-methylnicotinamide, nicotine imine and N-Methylnicotinium in nails of oral cancer patients and prediction of them as modulators of DNMT1

Dutta

Kumar

Lokhande

et al. 2020

Preprint

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Background The prominent among various existing views on the role of nicotine and nicotine-metabolized products in Oral squamous cell carcinoma (OSSC) is metabolic adaptation that allows the use of methyl-donor S-adenosylmethionine (SAM) for non-epigenetic purpose including the methylation of nicotinamide and nicotine. In fact, channeling of SAM for generation of 1-methylnicotinamide (1-MNA) and methylated nicotine products is seen as a key event in cancer cells that allows favorable epigenetic states by forcing DNA hypomethylation. A better perception of such events can be appreciated by analyzing samples like nail, which represents a perfect biological material for studying long-term metabolic reflections of the body. Methods Potential nicotine-metabolized products and 1-MNA in nails of OSCC patients were analyzed by using a novel approach of Vertical tube gel electrophoresis (VTGE)- assisted purification followed by their identification by LC-HRMS. Further, these identified nicotine metabolized products and 1-MNA were evaluated for their molecular interactions with known methyltransferases including cytosolic nicotinamide methyltransferase (NNMT), DNA methyltransferase (DNMT)1 and histone methyltransferases by molecular docking and molecular dynamics simulation (MDS) analyses. Results Our data suggests the presence of N-methylnicotinium ion and nicotine imine in the nail samples of OSCC patients. Further, 1-MNA is also detected in the nails as a major enzymatic product of a known detoxifying enzyme NNMT. Molecular docking of all nicotine and nicotine metabolized products with DNMT1revealed a specific binding affinity of nicotine imine only with a -6.2 Kcal/Mol docking energy. Importantly, binding of nicotine imine is within the CXCC regulatory domain of DNMT1 and it displays molecular interactions with the key amino acid residues, namely ARG690, PRO574, VAL658, PRO692 and ALA695. Furthermore, MDS data corroborated well with the specific binding affinity of nicotine imine to DNMT1 obtained by docking analysis. Conclusion Identification of N-methylnicotinium ion, nicotine imine and 1-MNA in nail samples indicates their potential as predictive and detectable biomarkers for OSCC. Molecular docking and MDS data lead us to propose a role of nicotine imine in modulating the activity of DNMT1. These data further suggest a novel understanding on the role of nicotine metabolized products in modulating DNA methylation that may contribute to tumorigenicity in oral cancer patients.

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“…3 However, in in vivo studies, DNMT1 has been shown the de novo DNA methylation activity. 3,4 DNMT3a and DNMT3b are classic de novo DNMTs and these DNMTs play a role in de novo methylation of genomic sequences. 3 In healthy cells, most of the CpG islands localized in promotor regions and important for expression of genes in the presence of the required transcriptional activator.…”

Section: Dna Methylation and Histone Modification In Normal Cellsmentioning

confidence: 99%

“… 3 However, in in vivo studies, DNMT1 has been shown the de novo DNA methylation activity. 3 4 DNMT3a and DNMT3b are classic de novo DNMTs and these DNMTs play a role in de novo methylation of genomic sequences. 3 …”

Section: Introductionmentioning

confidence: 99%

Cancer Treatment: An Epigenetic View

Aydin

Kalkan

2020

Global Medical Genetics

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Cancer can be identified as an uncontrolled growth and reproduction of cell. Accumulation of genetic aberrations (mutations of oncogenes and tumor-suppressor genes and epigenetic modifications) is one of the characteristics of cancer cell. Increasing number of studies highlighted importance of the epigenetic alterations in cancer treatment and prognosis. Now, cancer epigenetics have a huge importance for developing novel biomarkers and therapeutic target for cancer. In this review, we will provide a summary of the major epigenetic changes involved in cancer and preclinical results of epigenetic therapeutics.

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DNA methyltransferases: emerging targets for the discovery of inhibitors as potent anticancer drugs

Cited by 51 publications

References 67 publications

Systematic Analysis of Coronavirus Disease 2019 (COVID-19) Receptor ACE2 in Malignant Tumors: Pan-Cancer Analysis

Systematic Analysis of Coronavirus Disease 2019 (COVID-19) Receptor ACE2 in Malignant Tumors: Pan-Cancer Analysis

Detection of oncometabolites 1-methylnicotinamide, nicotine imine and N-Methylnicotinium in nails of oral cancer patients and prediction of them as modulators of DNMT1

Cancer Treatment: An Epigenetic View

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