Clinical significance of the expression of DNA methyltransferase proteins in gastric cancer

Yang, Jian; Wei, Xiaowei; Wu, Qiaobing; Xu, Zhi; Gu, Dongying; Jin, Yan; Shen, Ya; Huang, Huaying; Fan, Hong; Chen, Jinfei

doi:10.3892/mmr.2011.578

Cited by 31 publications

(21 citation statements)

References 18 publications

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“…Some studies demonstrated that there is a coordinate action of the DNMTs. 32,33 In accordance, a significant correlation between the expression of these enzymes was observed in the present study, suggesting that there is a cooperative action of the DNMTs expression in pediatric MDS pathogenesis.…”

Section: Discussionsupporting

confidence: 89%

<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

Lovatel¹,

Fernandez²,

Rodrigues³

et al. 2020

CMAR

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The aim of this study was to analyse the expression profiles of DNMT1, DNMT3A, DNMT3B (components of DNA methylation machinery), TET2 and APOBEC3B (components of DNA demethylation machinery) in pediatric MDS patients and investigate their associations with MDS subtypes, cytogenetics, evolution to acute myeloid leukemia (AML) and p15 INK4B methylation level. Patients and Methods: The expressions of DNMT1, DNMT3A, DNMT3B, TET2, and APOBEC3B were evaluated in 39 pediatric MDS patients by real-time quantitative PCR (qPCR). The quantification of p15 INK4B methylation levels (MtL) was performed in 20 pediatric MDS patients by pyrosequencing. Mann-Whitney test was used to evaluate possible differences between the expression levels of selected in patients and donors, according to MDS subtypes, karyotypes, evolution to AML and p15 INK4B MtL. The correlations between the expression levels of the different genes were assessed by Spearman rank correlation coefficient. Results: We found that DNMTs expression levels were higher in pediatric MDS compared to donors [DNMT1 (p<0.03), DNMT3A (p<0.03), DNMT3B (p<0.02)]. TET2 and APOBEC3B expression levels did not show a statistically significant difference between pediatric patients and donors. Considering MDS subtypes, patients at initial stage presented DNMT1 overexpression (p<0.01), while DNMT3A (p<0.02) and DNMT3B (p<0.007) were overexpressed in advanced subtypes. TET2 and APOBEC3B expression did not differ in MDS subtypes. DNMT1 (p<0.03), DNMT3B (p<0.03), and APOBEC3B (p<0.04) expression was higher in patients with normal karyotypes, while patients with abnormal karyotypes showed higher DNMT3A expression (p<0.03). Karyotypes had no association with TET2 expression. DNMTs overexpression was observed in patients who showed disease evolution. A positive correlation was found between DNMTs expression and between APOBEC3B and DNMT3A/DNMT3B. However, TET2 expression was not correlated with DNMTs or APOBEC3B. p15 INK4B MtL was higher in pediatric MDS patients compared with donors (p<0.03) and its hypermethylation was associated with increased DNMT1 expression (p<0.009). Conclusion: Our results suggest that the overexpression of DNMTs and an imbalance between the expressions of the DNA methylation/demethylation machinery components play an important role in MDS development and evolution to AML. These results have clinical implications indicating the importance of DNMTs inhibitors for preventing or delaying the progression to leukemia in pediatric MDS patients.

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Section: Discussionsupporting

confidence: 89%

<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

Lovatel¹,

Fernandez²,

Rodrigues³

et al. 2020

CMAR

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“…DNMTs were a predominant cause of DNA methylation and the differential expression of DNMTs has been identified in numerous types of cancer (41–43), including EOC, which we previously reported (32). It was hypothesized in the present study that the over-expression of DNMT proteins may contribute to BRCA1 methylation; therefore, the association between BRCA1 methylation and DNMT protein expression was analyzed.…”

Section: Discussionmentioning

confidence: 56%

BRCA1 promoter hypermethylation in sporadic epithelial ovarian carcinoma: Association with low expression of BRCA1, improved survival and co-expression of DNA methyltransferases

Bai

Xue

et al. 2014

Oncology Letters

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The breast cancer susceptibility gene 1 (BRCA1) inactivation in sporadic epithelial ovarian carcinoma (EOC) is common and low BRCA1 expression is associated with promoter hypermethylation. The clinical validation of BRCA1 methylation as a prognostic marker in EOC remains unresolved. The aim of the present study was to determine the aberrant promoter methylation of BRCA1 in benign and malignant ovarian tumor tissues, to establish the association with the clinicopathological significance and the prognostic value. Additionally, the contribution of DNA methyltransferase (DNMT) expression to BRCA1 promoter hypermethylation was determined. The rate of BRCA1 methylation was observed to be 35.2% (50/142) in the EOCs; however, no methylation (0/32) was observed in the benign tumors. BRCA1 methylation was significantly associated with the downregulation of BRCA1 expression (P<0.001) and the frequency of BRCA1 methylation was greater in the carcinomas of patients whose tumor was bilateral than that of patients with a unilateral carcinoma (P=0.015). BRCA1 methylation was significantly associated with the preoperative serum carbohydrate antigen-125 level (P=0.013), improved overall survival (P=0.005) and disease-free survival (P=0.007). In addition, a significant correlation was observed between the co-expression of DNMTs and the methylation status of BRCA1. Thus, the present study provided support for BRCA1 promoter hypermethylation as a prognostic marker for survival in sporadic EOC, and co-expression of DNMTs was observed to contribute to BRCA1 promoter hypermethylation.

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“…In eukaryotic cells, there are three enzymatically active DNA methyltransferases (DNMTs), DNMT1, DNMT3A and DNMT3B. The expression of DNMT3A in GC is significantly higher than that of DNMT3B [ 32 , 33 ]. Moreover, only increased DNMT3A expression is significantly associated with a shorter disease-free survival period in GC [ 34 ], which indicates DNMT3A plays more important roles in gastric carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Deregulation between miR-29b/c and DNMT3A Is Associated with Epigenetic Silencing of the CDH1 Gene, Affecting Cell Migration and Invasion in Gastric Cancer

Gong

Zhao

et al. 2015

PLoS ONE

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The de-regulation of the miR-29 family and DNA methyltransferase 3A (DNMT3A) is associated with gastric cancer (GC). While increasing evidence indicates miR-29b/c could regulate DNA methylation by targeting DNMT3A, it is currently unknown if epigenetic silencing of miR-29b/c via promoter hypermethylation in GC is caused by abnormal expression of DNMT3A. Thus, we aimed to evaluate whether cross-talk regulation exists between miR-29b/c and DNMT3A and whether it is associated with a malignant phenotype in GC. First, wound healing and Transwell assays revealed that miR-29b/c suppresses tumor metastasis in GC. A luciferase reporter assay demonstrated that DNMT3A is a direct target of miR-29b/c. We used bisulfite genomic sequencing to analyze the DNA methylation status of miR-29b/c. The percentage of methylated CpGs was significantly decreased in DNMT3A-depleted cells compared to the controls. Furthermore, the involvement of DNMT3A in promoting GC cell migration was associated with the promoter methylation-mediated repression of CDH1. In 50 paired clinical GC tissue specimens, decreased miR-29b/c was significantly correlated with the degree of differentiation and invasion of the cells and was negatively correlated with DNMT3A expression. Together, our preliminary results suggest that the following process may be involved in GC tumorigenesis. miR-29b/c suppresses the downstream gene DNMT3A, and in turn, miR-29b/c is suppressed by DNMT3A in a DNA methylation-dependent manner. The de-regulation of both of miR-29b/c and DNMT3A leads to the epigenetic silencing of CDH1 and contributes to the metastasis phenotype in GC. This finding reveals that DNA methylation-associated silencing of miR-29b/c is critical for GC development and thus may be a therapeutic target.

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Clinical significance of the expression of DNA methyltransferase proteins in gastric cancer

Cited by 31 publications

References 18 publications

<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

BRCA1 promoter hypermethylation in sporadic epithelial ovarian carcinoma: Association with low expression of BRCA1, improved survival and co-expression of DNA methyltransferases

Deregulation between miR-29b/c and DNMT3A Is Associated with Epigenetic Silencing of the CDH1 Gene, Affecting Cell Migration and Invasion in Gastric Cancer

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