Expression of DNA methyltransferases in multistep hepatocarcinogenesis

Choi, Mi Sun; Shim, Yhong–Hee; Hwa, Jung; Lee, Seung Kyu; Ro, Jae Y.; Kim, Jung sun; Yu, Eunsil

doi:10.1053/hupa.2003.5

Cited by 62 publications

(36 citation statements)

References 30 publications

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“…nuclear expression of DnMt3a was observed in only three samples of oKc, mainly in the suprabasal layers. It has been demonstrated in hepatocarcinogenesis, the sequential decrease in cytoplasmic immunoreactivity for DnMt3a, as well as the concurrent increase in nuclear DnMt3a in high-grade dysplasia and carcinomas when compared to non-neoplastic and low-grade dysplasia (18). The biological significance of nuclear staining has yet to be established, but since methylation occurs inside the nuclei, we hypothesize that the nuclear expression (11).…”

Section: Discussionmentioning

confidence: 99%

DNA methyltransferase expression in odontogenic cysts and tumours

Gomes

Brito²,

Andrade³

et al. 2010

Oncology Letters

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Abstract. epigenetic silencing of gene expression by promoter cpg island hypermethylation is promoted by the enzymes, DnA methyltransferases (DnMts). DnMt3a is mainly involved in de novo methylation, whereas DnMt1 acts mainly as a maintenance methyltransferase. the purpose of this study was to investigate the immunoexpression of DnMt1 and DnMt3a in a set of odontogenic cysts and tumours. Formalin-fixed and paraffin-embedded tissue samples of eight radicular cysts, 10 odontogenic keratocysts (oKc), eight adenomatoid odontogenic tumours (Aot), 16 ameloblastomas and eight samples of normal mucosae were included in the study. The DNMT1 and DNMT3a proteins were identified by using a highly sensitive polymer-based system. We found that the normal oral mucosa, oKc, Aot, radicular cyst and ameloblastomas samples showed a widespread nuclear and cytoplasmic immunopositivity for DnMt1. some radicular cysts, ameloblastomas, Aot and oKc samples presented a positive cytoplasmic reaction for DnMt3a, while negative staining was observed in the normal oral mucosa. nuclear positivity was found only in the suprabasal cell layers of three oKc samples. our study shows an increased expression of DNMT3a in odontogenic cysts and tumours, confirming that epigenetic mechanisms are involved in the development of these tumours.

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Section: Discussionmentioning

confidence: 99%

DNA methyltransferase expression in odontogenic cysts and tumours

Gomes

Brito²,

Andrade³

et al. 2010

Oncology Letters

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“…Using real-time PCR and Western blot techniques, Xiong et al [30] have found increased DNMT1 expression in grade III endometrioid cancers. In addition, and by immunohistochemistry, DNMT1 expression was found to be increased significantly in high-grade hepatocellular carcinomas, suggesting that DNMT1 overexpression plays a role in the early stage of hepatocarcinogenesis [20]. Using semiquantitative reverse transcription-PCR, Chen et al [9] have demonstrated that DNMT1 overexpression in ovarian epithelial cancers was correlated with low tumor differentiation, advanced clinical stage, and lymphatic metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Z.) using a semiquantitative scoring system [20] taking into consideration the staining intensity obtained (0, negative; 1, mild; 2, moderate; 3, high) and the proportion of positive cells observed (0, negative; 1, ≤10%; 2, 11% to ≤33%; 3, 34% to ≤66%; 4, ≥66%). The 2 scores were then added for each slide, and overexpression was defined as grade 6 or greater.…”

Section: Immunohistochemical Analysis Of Dnmts Expressionmentioning

confidence: 99%

Clinicopathologic significance of DNA methyltransferase 1, 3a, and 3b overexpression in Tunisian breast cancers

et al. 2012

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Summary DNA methyltransferase 1, 3a, and 3b affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers. The current study was designed to analyze DNA methyltransferase expression by immunohistochemistry in a series of 94 Tunisian sporadic breast carcinomas. Results were correlated to clinicopathologic parameters and promoter methylation status of 8 tumor suppressor genes (BRCA1, BRCA2, RASSFA1, TIMP3, CDH1, P16, RARβ2, and DAPK). Overexpression of DNA methyltransferase 1, 3a, and 3b was detected in 46.8%, 32%, and 44.7% of cases, respectively. A significant correlation was found between DNA methyltransferase 1 overexpression and Scarff-Bloom-Richardson histologic grade III (P = .01). DNA methyltransferase 3a overexpression was significantly associated with menopausal status (P = .01), Scarff-Bloom-Richardson histologic grade III (P = .0001), estrogen (P = .04) and progesterone (P = .007) receptor negativity, and HER2 overexpression (P = .004). However, DNA methyltransferase 3a overexpression was found less frequently in the luminal A intrinsic breast cancer subtype (9.7%) than in luminal B (53%), HER2 (41%), and triple-negative (50%) subtypes (P = .001). DNA methyltransferase 3b overexpression shows significant correlation with promoter hypermethylation of BRCA1 (P = .03) and RASSFA1 (P = .04) and with the hypermethylator phenotype (more than 4 methylated genes, P = .01). These data suggest that overexpression of various DNA methyltransferases might represent a critical event responsible for the epigenetic inactivation of multiple tumor suppressor genes, leading to the development of aggressive forms of sporadic breast cancer.

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“…Mouse studies have shown that both Dnmt3a and Dnmt3b are required for the establishment and maintenance of genomic methylation patterns and proper murine development (Bachman et al, 2001;Gowher and Jeltsch, 2002;Kaneda et al, 2004). DNMT3A and DNMT3B are upregulated in certain types of hematological malignancies and solid tumors, including leukocythemia (Mizuno et al, 2001;Claus and Lubbert, 2003), colorectal cancer Takeshima et al, 2006), lung cancer, breast cancer (Girault et al, 2003;Shafiei et al, 2008) and HCC (Saito et al, 2002;Choi et al, 2003). Specifically, DNMT3B contributes to oncogenic phenotypes (Linhart et al, 2007) and tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing (Wang et al, 2007).…”

Section: Introductionmentioning

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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Expression of DNA methyltransferases in multistep hepatocarcinogenesis

Cited by 62 publications

References 30 publications

DNA methyltransferase expression in odontogenic cysts and tumours

DNA methyltransferase expression in odontogenic cysts and tumours

Clinicopathologic significance of DNA methyltransferase 1, 3a, and 3b overexpression in Tunisian breast cancers

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

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