scholarly journals DNMT family induces down-regulation of NDRG1 via DNA methylation and clinicopathological significance in gastric cancer

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12146
Author(s):  
Xiaojing Chang ◽  
Jinguo Ma ◽  
Xiaoying Xue ◽  
Guohui Wang ◽  
Tianfang Yan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Analysis Data ◽  
Sequencing Analysis ◽  
Invasion Depth ◽  
Down Regulation ◽  
Invasion And Migration ◽  
Target Drug ◽  
Dnmt Family

Background Aberrant DNA methylation of tumor suppressor genes is a common event in the development and progression of gastric cancer (GC). Our previous study showed NDRG1, which could suppress cell invasion and migration, was frequently down-regulated by DNA methylation of its promoter in GC. Purpose and Methods To analyze the relationship between the expression and DNA methylation of NDRG1 and DNA methyltransferase (DNMT) family. We performed a comprehensive comparison analysis using 407 patients including sequencing analysis data of GC from TCGA. Results NDRG1 was down-regulated in GC, and was negatively correlative to DNMT1 (r = −0.11, p = 0.03), DNMT3A (r = −0.10, p = 0.01), DNMT3B (r = −0.01, p = 0.88), respectively, whereas the DNA methylation of NDRG1 was positively correlative to DNMT family (DNMT1 r = 0.20, p < 0.01; DNMT3A r = 0.26, p < 0.001; DNMT3B r = 0.03, p = 0.57, respectively). NDRG1 expression was significantly inverse correlated with invasion depth (p = 0.023), but DNMT1 was significantly positive correlated with invasion depth (p = 0.049). DNMT3B was significantly correlated with the degree of tumor cell differentiation (p = 0.030). However, there was no association between the expression of DNMT3A and clinicopathological features. The KM plotter showed that NDRG1 (HR = 0.95, 95% CI [0.8–1.12], p = 0.53) and DNMT1 (HR = 1.04, 95% CI [0.88–1.23], p = 0.67) had no association with prognosis of GC patients, while, DNMT3A (p = 0.0064) and DNMT3B (p = 0.00025) displayed significantly association. But the overall survival of high expression of NDRG1 tended to be prolonged. Conclusion These data suggest that down-regulation of NDRG1expression in GC may be due to its promoter DNA methylation via DNMT family. The demethylating agent maybe a potential target drug for GC patients.

scholarly journals DNMT family induced down-regulation of NDRG1 via DNA methylation and clinicopathological significance in gastric cancer

2021 ◽  
Author(s):  
Xiaojing Chang ◽  
Jinguo MA ◽  
Xiaoying Xue ◽  
Guohui Wang ◽  
Linlin Su ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Cell Differentiation ◽  
Tumor Cell ◽  
Dna Methyltransferase ◽  
Univariate Analysis ◽  
Sequencing Analysis ◽  
Down Regulation ◽  
Dnmt Family ◽  
Tumor Cell Differentiation

AbstractBackgroundAberrant DNA methylation of tumor suppressor genes is a common event in the development and progression of gastric cancer(GC). Our previous study showed NDRG1, which could suppress cell invasion and migration, was frequently down-regulated by DNA methylation of its promoter in GC.Purpose and MethodsTo analyze the relationship between the expression and DNA methylation of NDRG1 and DNA methyltransferase (DNMT) family. We performed a comprehensive comparison analysis using 407 patients including sequencing analysis data of GC from TCGA.ResultsNDRG1 was negatively correlative to DNMT1 (p =0.03), DNMT3A(p =0.01), DNMT3B(p =0.88), respectively. Whereas, the DNA methylation of NDRG1 was positively correlative to DNMT family(DNMT1 p<0.01, DNMT3A p<0.001, DNMT3B p=0.57, respectively). NDRG1 expression was significantly inverse correlated with invasion depth (p =0.023), and DNMT1 was significantly positive correlated with the degree of tumor cell differentiation (p =0.049). DNMT3B was significantly correlated with tumor cell differentiation (p =0.030). However, there was no association between the expression of DNMT3A and clinicopathological features. The univariate analysis showed that NDRG1and DNMTs had no association with prognosis of GC patients. But, multivariate analysis showed DNMT1 was significantly correlated with prognosis of GC patients.ConclusionThese data suggest that down-regulation of NDRG1 in gastric cancer is due to DNA methylation of NDRG1 gene promoter via DNMT family. The demethylating agent maybe a potential target drug for GC patients.

scholarly journals Evolutionary analysis of DNA methyltransferases in microeukaryotes: Insights from the model diatom Phaeodactylum tricornutum

2021 ◽  
Author(s):  
ANTOINE HOGUIN ◽  
Ouardia Ait Mohamed ◽  
Chris Bowler ◽  
Auguste Genovesio ◽  
Fabio RJ Vieira ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transposable Elements ◽  
Phaeodactylum Tricornutum ◽  
Dna Methyltransferase ◽  
Transcriptional Control ◽  
Dna Methyltransferases ◽  
Epigenetic Mark ◽  
Evolutionary Analysis ◽  
And Function ◽  
Dnmt Family

Cytosine DNA methylation is an important epigenetic mark in eukaryotes that is involved in the transcriptional control of mainly transposable elements in mammals, plants, and fungi. Eukaryotes encode a diverse set of DNA methyltransferases that were iteratively acquired and lost during evolution. The Stramenopiles-Alveolate-Rhizaria (SAR) lineages are a major group of ecologically important marine microeukaryotes that include the main phytoplankton classes such as diatoms and dinoflagellates. However, little is known about the diversity of DNA methyltransferases and their role in the deposition and maintenance of DNA methylation in microalgae. We performed a phylogenetic analysis of DNA methyltransferase families found in marine microeukaryotes and show that they encode divergent DNMT3, DNMT4, DNMT5 and DNMT6 enzymes family revisiting previously established phylogenies. Furthermore, we reveal a novel group of DNMTs with three classes of enzymes within the DNMT5 family. Using a CRISPR/Cas9 strategy we demonstrate that the loss of the DNMT5 gene correlates with a global depletion of DNA methylation and overexpression of transposable elements in the model diatom Phaeodactylum tricornutum. The study provides a pioneering view of the structure and function of a DNMT family in the SAR supergroup.

Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer

2020 ◽  
Vol 47 (8) ◽  
pp. 5721-5727
Author(s):  
Shiva Rezaei ◽  
Mohammad Ali Hosseinpourfeizi ◽  
Yaghoub Moaddab ◽  
Reza Safaralizadeh
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Down Regulation

scholarly journals Peperomin E Induces Promoter Hypomethylation of Metastatic-Suppressor Genes and Attenuates Metastasis in Poorly Differentiated Gastric Cancer

2018 ◽  
Vol 50 (6) ◽  
pp. 2341-2364 ◽  
Author(s):  
Xin-zhi  Wanga ◽  
Jia-li Gu ◽  
Ming Gao ◽  
Yong Bian ◽  
Jiang-yu Liang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Suppressor Genes ◽  
Invasion And Migration ◽  
Poorly Differentiated ◽  
And Migration

Background/Aims: Peperomin E (PepE), a natural secolignan isolated from the whole plant of Peperomia dindygulensis, has been reported by ourselves and others to display potent anti-cancer effects in many types cancer cells, especially gastric cancer. However, the effects of PepE on the metastasis of poorly-differentiated gastric cancer cells and the underlying molecular mechanisms have not been well elucidated. Methods: We evaluated PepE effects on gastric cancer cell invasion and migration in vitro via wound healing and transwell assays and those on growth and metastasis in vivo using an orthotopic xenograft NOD-SCID mouse model. DNA methyltransferase (DNMT) activity was determined using a colorimetric DNMT activity/inhibition assay kit. PepE binding kinetics to DNMTs were determined using the bio-layer interferometry binding assay. Gene and protein levels of DNMTs, AMPKα-Sp1 signaling molecules, and metastatic-suppressor genes in PepE-treated gastric cancer cells were determined using quantitative reverse transcription-PCR arrays and western blotting. The effect of PepE on Sp1 binding to the DNMT promoter was determined by electrophoretic mobility-shift assay. Global DNA methylation levels were determined using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The methylation status of silenced metastatic-suppressor genes (MSGs) in gastric cancer cells was investigated by methylation-specific PCR. Results: PepE can dose-dependently suppress invasion and migration of poorly-differentiated gastric cancer cells in vitro and in vivo with low toxicity against normal cells. Mechanistically, PepE not only covalently binds to the catalytic domain of DNMT1 and inhibits its activity (IC50 value 3.61 μM) but also down-regulates DNMT1, 3a, and 3b mRNA and protein expression in in gastric cancer cells, by disruption of the physical interaction of Sp1 with the DNMT1, 3a, and 3b promoter and mediation of the AMPKα-Sp1 signaling pathway. The dual inhibition activity of PepE toward DNMTs renders a relative global DNA hypomethylation, which induces MSG promoter hypomethylation (e.g., E-cadherin and TIMP3) and enhances their expression in gastric cancer cells. Conclusion: Collectively, our data indicated that PepE may represent a promising therapeutic lead compound for intervention in gastric cancer metastasis and may also exhibit potential as a DNA methylation inhibitor for use in epigenetic cancer therapy.

scholarly journals Inhibition of DNMT1 and ERRα crosstalk suppresses breast cancer via derepression of IRF4

Oncogene ◽  
2020 ◽  
Vol 39 (41) ◽  
pp. 6406-6420
Author(s):  
Mathieu Vernier ◽  
Shawn McGuirk ◽  
Catherine R. Dufour ◽  
Liangxinyi Wan ◽  
Etienne Audet-Walsh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Large Scale ◽  
Transcriptional Control ◽  
Critical Role ◽  
Promoter Hypermethylation ◽  
Sequencing Analysis

Abstract DNA methylation is implicated in the acquisition of malignant phenotypes, and the use of epigenetic modulating drugs is a promising anti-cancer therapeutic strategy. 5-aza-2’deoxycytidine (decitabine, 5-azadC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor with proven effectiveness against hematological malignancies and more recently triple-negative breast cancer (BC). Herein, genetic or pharmacological studies uncovered a hitherto unknown feedforward molecular link between DNMT1 and the estrogen related receptor α (ERRα), a key transcriptional regulator of cellular metabolism. Mechanistically, DNMT1 promotes ERRα stability which in turn couples DNMT1 transcription with that of the methionine cycle and S-adenosylmethionine synthesis to drive DNA methylation. In vitro and in vivo investigation using a pre-clinical mouse model of BC demonstrated a clear therapeutic advantage for combined administration of the ERRα inhibitor C29 with 5-azadC. A large-scale bisulfite genomic sequencing analysis revealed specific methylation perturbations fostering the discovery that reversal of promoter hypermethylation and consequently derepression of the tumor suppressor gene, IRF4, is a factor underlying the observed BC suppressive effects. This work thus uncovers a critical role of ERRα in the crosstalk between transcriptional control of metabolism and epigenetics and illustrates the potential for targeting ERRα in combination with DNMT inhibitors for BC treatment and other epigenetics-driven malignancies.

scholarly journals Comprehensive Analysis of DNA Methylation Regulator DNA Methyltransferase (DNMT) Family and Ten-Eleven-Translocation (TET) Enzymes Family in Pan-Cancer

2021 ◽  
Author(s):  
Cheng Ouyang ◽  
Hao Li ◽  
Liping Sun
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Dna Methyltransferase ◽  
Copy Number Variations ◽  
Cholesterol Homeostasis ◽  
The Cancer Genome Atlas ◽  
Cancer Types ◽  
Tet Genes ◽  
Pan Cancer ◽  
Dnmt Family

Abstract Background: DNA methyltransferase (DNMT) family and ten-eleven-translocation (TET) family enzymes play pivotal roles in regulating DNA methylation, and are closely related to diverse cancers. This study was designed to clarify the specific roles of DNMT and TET genes in pan-cancers.Methods: The expression, mutation, copy number variations (CNVs), cancer-related pathways, immune cell infiltration correlation, and prognostic potential of DNMT/TET genes were systematically investigated in 33 cancer types using next-generation sequence data from the Cancer Genome Atlas database. Results: DNMT3B was more highly expressed in the majority of tumors analyzed than in normal tissues. Most DNMT/TET genes were frequently mutated in uterine carcinosarcoma, and TET1 and TET2 showed higher mutation frequencies in various cancer types. DNMT3B exhibited inclusive copy number amplification in almost all cancers, such as stomach adenocarcinoma(STAD) and colon adenocarcinoma(COAD)l, while most DNMT/TET genes displayed highly copy number deletion in kidney chromophobe（KICH）. DNMT/TET genes were mainly involved in the following cancer-related pathways: UV response DN, mitotic spindle, cholesterol homeostasis, TGF beat signaling, xenobiotic metabolism, G2/M checkpoint, and E2F targets. DNMT/TET genes were significantly correlated with NK cells, CD4 positive T cells, and Tfh cells. Additionally, Most DNMT/TET genes were significantly associated with lower survival rates of adrenocortical carcinoma (ACC), mesothelioma, and liver hepatocellular carcinoma (LIHC), but played a protective role in thymoma (THYM). Furthermore, overexpression of most DNMT genes, except for DMAP1, was associated worse prognoses in pan-cancer. Conclusion: These results suggest that DNMT/TET genes can serve as potential predictors for prognosis and treatment in pan-cancer, providing new insight for future study.

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