Expression and function role of DNA methyltransferase 1 in human bladder cancer

Wu, Chun–Te; Wu, Ching-Yang; Lu, Chang‐Hsien; Lin, Chun-Li; Chen, Wen‐Cheng; Lin, Pyng Jing; Chen, Miao‐Fen

doi:10.1002/cncr.26150

Cited by 41 publications

(54 citation statements)

References 46 publications

(57 reference statements)

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“…The overexpression of DNMT1 in BLCA [43], has already been shown in previous studies. However, its association with smoking has not been demonstrated.…”

Section: Discussionmentioning

confidence: 62%

RETRACTED: Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer

Jin

Thaiparambil

Donepudi

et al. 2017

Cancer Prevention Research

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Smoking is a major risk factor for the development of Bladder Cancer (BLCA); however, the functional consequences of the carcinogens in tobacco smoke and BLCA-associated metabolic alterations remains poorly defined. We assessed the metabolic profiles in BLCA smokers and non-smokers, and identified the key alterations in their metabolism. Liquid Chromatography – Mass Spectrometry (LC-MS), and bioinformatic analysis were performed to determine the metabolome associated with BLCA smokers and were further validated in cell line models. Smokers with BLCA were found to have elevated levels of methylated metabolites, polycyclic aromatic hydrocarbons (PAHs), DNA adducts and DNA damage. DNA methyltransferase 1 (DNMT1) expression was significantly higher in smokers than non-smokers with BLCA. An integromics approach, using multiple patient cohorts, revealed strong associations between smokers and high-grade BLCA. In vitro exposure to the tobacco smoke carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP) led to increase in levels of methylated metabolites, DNA adducts, and extensive DNA damage in BLCA cells. Co-treatment of BLCA cells with these carcinogens and the methylation inhibitor 5-aza-2′-deoxycytidine (AZA) rewired the methylated metabolites, DNA adducts, DNA damage. These findings were confirmed through the isotopic labeled metabolic flux analysis. Screens using smoke associated metabolites and DNA adducts could provide robust biomarkers and improve individual risk prediction in BLCA smokers. Non-invasive predictive biomarkers that can stratify the risk of developing BLCA in smokers could aid in early detection and treatment.

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“…The overexpression of DNMT1 in BLCA [43], has already been shown in previous studies. However, its association with smoking has not been demonstrated.…”

Section: Discussionmentioning

confidence: 62%

RETRACTED: Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer

Jin

Thaiparambil

Donepudi

et al. 2017

Cancer Prevention Research

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“…In our study, the DNMT1 mRNA level was significantly higher (52%) in T2-T4 compared with Ta/T1 (16%) tumors. These findings are complementary and similar to the results reported by Wu et al [60] and confirm high expression of DNMT1 in invasive bladder cancer. As DNMT1 can participate in multiple complex networks involved in epigenetic signaling and genome stability including interaction with MLH1 and MBD4 [63], in our study, we compared the mRNA expression of these genes with each other.…”

Section: Discussionsupporting

confidence: 80%

“…On the contrary, 24% of early stage tumors (CIS, Ta, T1) and 15% of nonmalignant bladder tissues expressed DNMT1 [60]. Immunohistochemical staining demonstrated a positive correlation between tumor invasion depth and DNMT1 expression [60]. In our study, the DNMT1 mRNA level was significantly higher (52%) in T2-T4 compared with Ta/T1 (16%) tumors.…”

Section: Discussionmentioning

confidence: 65%

“…Namely, 55% of T2-T4 bladder cancer tissues had positive staining for DNMT1. On the contrary, 24% of early stage tumors (CIS, Ta, T1) and 15% of nonmalignant bladder tissues expressed DNMT1 [60]. Immunohistochemical staining demonstrated a positive correlation between tumor invasion depth and DNMT1 expression [60].…”

Section: Discussionmentioning

confidence: 99%

“…DNA methylation is typically mediated by DNMT1 (maintenance methyltransferase) as well as DNMT3A and DNMT3B ( de novo methyltransferases) [59, 60]. In addition, DNMT1, but not the DNMT3, seems to play a role in the MMR pathway [61].…”

Section: Discussionmentioning

confidence: 99%

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Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer

Wojtczyk-Miaskowska

Presler

Michajłowski

et al. 2017

Cell Physiol Biochem

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Background/Aims: This study investigated the gene expression and DNA methylation of selected DNA repair genes (MBD4, TDG, MLH1, MLH3) and DNMT1 in human bladder cancer in the context of pathophysiological and prognostic significance. Methods: To determine the relationship between the gene expression pattern, global methylation and promoter methylation status, we performed real-time PCR to quantify the mRNA of selected genes in 50 samples of bladder cancer and adjacent non-cancerous tissue. The methylation status was analyzed by methylation-specific polymerase chain reaction (MSP) or digestion of genomic DNA with a methylation-sensitive restriction enzyme and PCR with gene-specific primers (MSRE-PCR). The global DNA methylation level was measured using the antibody-based 5-mC detection method. Results: The relative levels of mRNA for MBD4, MLH3, and MLH1 were decreased in 28% (14/50), 34% (17/50) and 36% (18/50) of tumor samples, respectively. The MBD4 mRNA expression was decreased in 46% of non-muscle invasive tumors (Ta/T1) compared with 11% found in muscle invasive tumors (T2-T4) (P<0.003). Analysis of mRNA expression for TDG did not show any significant differences between Ta/T1 and T2-T4 tumors. The frequency of increased DNMT1 mRNA expression was higher in T2-T4 (52%) comparing to Ta/T1 (16%). The overall methylation rates in tumor tissue were 18% for MBD4, 25% for MLH1 and there was no evidence of MLH3 promoter methylation. High grade tumors had significantly lower levels of global DNA methylation (P=0.04). There was a significant association between shorter survival and increased expression of DNMT1 mRNA (P=0.002), decreased expression of MLH1 mRNA (P=0.032) and the presence of MLH1 promoter methylation (P=0.006). Conclusion: This study highlights the importance of DNA repair pathways and provides the first evidence of the role of MBD4 and MLH3 in bladder cancer. In addition, our findings suggest that DNMT1 mRNA and MLH1 mRNA expression, as well as the status of MLH1 promoter methylation, are attractive prognostic markers in this pathology.

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The role of DNA methyltransferase 3b in esophageal squamous cell carcinoma

Chen¹,

Lu²,

Lin³

et al. 2011

Cancer

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BACKGROUND:The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy-three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression. RESULTS: The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P ¼ .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates (P ¼ .002) and reduced survival rates (P ¼ .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial-mesenchymal-transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b-positive esophageal cancer. CONCLUSIONS: DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance. Cancer 2012;118:4074-

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Expression and function role of DNA methyltransferase 1 in human bladder cancer

Cited by 41 publications

References 46 publications

RETRACTED: Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer

RETRACTED: Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer

Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer

The role of DNA methyltransferase 3b in esophageal squamous cell carcinoma

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