An Essential Role for DNA Methyltransferase DNMT3B in Cancer Cell Survival

Beaulieu, Normand; Morin, Steves; Chute, Ian C.; Robert, Mathieu; Nguyen, Hannah; MacLeod, A. Robert

doi:10.1074/jbc.m204734200

Cited by 143 publications

(113 citation statements)

References 32 publications

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“…As a result of its de novo methyltransferase activity, DNMT3b is an attractive candidate for the other DNMT that contributes to tumor suppressor gene silencing. In support of this notion, antisense suppression of DNMT3b in tumor cell lines restored tumor suppressor gene expression (Beaulieu et al, 2002) as did deletion of DNMT3b in DNMT1-deficient HCT116 (Rhee et al, 2002). Nonetheless, the precise contribution of DNMT3b to tumor progression and transformation is unknown.…”

Section: Introductionmentioning

confidence: 64%

DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras

2003

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Transcriptional silencing of tumor suppressor genes in association with DNA methylation contributes to malignant transformation. However, the specific DNA methyltransferases that initiate this process are unknown. Here we show that a de novo DNA methyltransferase, DNMT3b, substantially contributes to the oncogenic phenotype in a lung cancer model. Normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and activated Ras were immortal, formed colonies in soft agar, and expressed DNMT3b. Antisense suppression of DNMT3b prevented soft agar growth. Furthermore, mouse embryo fibroblasts expressing T antigen and Ras formed soft agar colonies and large tumors, but fibroblasts from Dnmt3b À/À mice did not grow in soft agar and were much less tumorigenic in vivo. The tumor suppressor genes, FHIT, TSLC1, and RASSF1A were downregulated in transformed NHBE cells, and antisense DNMT3b treatment resulted in reexpression of FHIT and TSLC1. While expression of TSCL1 correlated with methylation of CpG dinucleotides in its promoter region, the expression of FHIT did not, suggesting that DNMT3b may silence genes by several mechanisms including direct DNA methylation or recruitment of proteins that modify chromatin. Regardless of mechanism, our data indicate that DNMT3b plays an important role in transformation.

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Section: Introductionmentioning

confidence: 64%

DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras

2003

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“…Unlike DNMT1, DNMT3b has been suggested to be site-selective in the regulation of aberrant gene silencing. DNMT3b expression has also been found to be essential for cancer cell survival by inhibiting apoptosis of tumour cells but not normal cells (Beaulieu et al, 2002). The results of in vitro studies by Geiman et al (2004) further indicate that DNMT3b contributes to gene silencing by recruiting chromatin remodeling histone deacetylase.…”

Section: Discussionmentioning

confidence: 95%

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

Xing

Stewart

et al. 2008

Br J Cancer

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The abnormality of DNA methylation is involved in tumour progression, and thus has a modulating effect on clinical outcome of cancer patients. In this study, we measured the mRNA expression levels of three methylation-regulating genes (DNMT1, DNMT3b, and MBD2) in 148 tumour samples from patients with non-small cell lung cancer (NSCLC) using quantitative real-time polymerase chain reaction and then determined their prognostic values. Our data showed that the high level of DNMT1 expression was significantly associated with an increased risk of death in all NSCLC patients (hazard ratio (HR), 1.74; 95% confidence interval (95% CI), 1.04 -2.90). However, the high level of DNMT3b expression was significantly associated with poor prognosis only in young patients (o65 years). The high level of MBD2 expression had a significantly reduced risk for death only in male patients and in squamous cell lung carcinoma (SQLC) patients. All three combination groups with DNMT1 and DNMT3b, DNMT1 and MBD2 or DNMT3b and MBD2 revealed significant combined effects in male patients and SQLC patients. Our results suggest that DNMT1, DNMT3b, and MBD2 may play important roles in modulating NSCLC patient survival and thus be useful for identifying NSCLC patients who would benefit most from aggressive therapy.

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“…An early in vitro study using the colon carcinoma cell line HCT116 reported that DNMT3B interacts with DNMT1 to silence gene expression in human cancer cells (Rhee et al, 2002). Recent studies have suggested that DNMT3B is required for tumor development (Beaulieu et al, 2002). Furthermore, DNMT3B1 efficiently methylates the same set of genes in both tumor and non-tumor tissues, demonstrating that the de novo methylation activity of methyltransferase 3B is essential to gene silencing.…”

Section: Discussionmentioning

confidence: 99%

MTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma

et al. 2011

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DNA methyltransferase 3B (DNMT3B) mediates gene silencing via epigenetic mechanisms during hepatocellular carcinoma (HCC) progression. We aimed to identify novel targets of DNMT3B and their potential regulatory mechanisms in HCC. Metastasis suppressor 1 (MTSS1) was one of the DNMT3B targets and selected for further study. DNMT3B overexpression was detected in 81.25% of clinical HCC specimens and was negatively associated with MTSS1 in HCC cells and clinical samples. The underlying mechanism by which DNMT3B silences MTSS1 was studied using a combination of methylation-specific polymerase chain reaction (PCR) and bisulfite genome sequencing, chromatin immunoprecipitation-PCR and luciferase reporter assays. We found that the MTSS1 promoter region was sparsely methylated, and the methylation inhibitors failed to abolish DNMT3B-mediated MTSS1 silencing. DNMT3B protein bound directly to the 5 0 -flanking region (À865/À645) of the MTSS1 gene to inhibit its transcription. The functional role of MTSS1 was investigated using in vitro and in vivo tumorigenicity assays. As a result, MTSS1 exerted tumor suppressor effects and arrested cells in the G2/M phase, but not the G1/S phase of the cell cycle when it was depleted or overexpressed in HCC cells. Taken together, MTSS1, a novel target of DNMT3B, is repressed by DNMT3B via a DNA methylation-independent mechanism. MTSS1 was further characterized as a novel tumor suppressor gene in HCC. These findings highlight how DNMT3B regulates MTSS1, and such data may be useful for the development of new treatment options for HCC.

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An Essential Role for DNA Methyltransferase DNMT3B in Cancer Cell Survival

Cited by 143 publications

References 32 publications

DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras

DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

MTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma

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