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Koul, Sanjay; Houldsworth, Jane; Mansukhani, Mahesh; Donadio, Alessia; McKiernan, James M.; Reuter, Victor E.; Bosl, George J.; Chaganti, R. S. K.; Murty, Vundavalli V.

doi:10.1186/1476-4598-1-8

Cited by 99 publications

(30 citation statements)

References 27 publications

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“…DNA hypermethylation contributes to the silencing of TSGs involved in testicular tumorigenesis. 24 Downregulation of miR-199a-3p allowed for increased DNMT3A2 expression, which could cause increased methylation. It was reasoned that the increased DNA methylation through this mechanism would hypermethylate some TSGs and facilitate the development of TGCT.…”

Section: Dnmt3a2 Is Significantly Upregulated In Nt2 Cells Compared Wmentioning

confidence: 99%

microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer

Chen

Suen

et al. 2013

Epigenetics

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It was previously demonstrated that miR-199a was downregulated in testicular germ cell tumor (TGCT), probably due to hypermethylation of its promoter. Further study found that re-expression of miR-199a in testicular cancer cells (NT2) led to suppression of cell growth, cancer migration, invasion and metastasis. More detailed analyses showed that these properties of miR-199a could be assigned to miR-199a-5p, one of its two derivatives. The biological role of the other derivative, miR-199a-3p in TGCT, remains largely uncharacterized. In this report, we identified DNA (cytosine-5)-methyltransferase 3A (DNMT3A), the de novo methyltransferase, as a direct target of miR-199a-3p using a 3'-UTR reporter assay. Transient expression of miR-199a-3p in NT2 cells led to decrease, while knocking down of miR-199a-3p in a normal human testicular cell line (HT) led to elevation, of DNMT3A2 (DNMT3A gene isoform 2) mRNA and protein levels. In clinical samples, DNMT3A2 was significantly overexpressed in malignant testicular tumor, and the expression of DNMT3A2 was inversely correlated with the expression of miR-199a-3p. However, DNMT3A did not affect miR-199a expression in NT2 cells. Further characterization of miR-199a-3p revealed that it negatively regulated DNA methylation, partly through targeting DNMT3A. Overexpression of miR-199a-3p restored the expression of APC and MGMT tumor-suppressor genes in NT2 cells by affecting DNA methylation of their promoter regions. Our studies demonstrated the deregulation of miR-199a-3p expression in TGCT may provide novel mechanistic insights into TGCT carcinogenesis and suggested a potentially therapeutic use of synthetic miR-199a-3p oligonucleotides as effective hypomethylating compounds in the treatment of TGCT.

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Section: Dnmt3a2 Is Significantly Upregulated In Nt2 Cells Compared Wmentioning

confidence: 99%

microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer

Chen

Suen

et al. 2013

Epigenetics

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“…At high doses, 5-aza-CdR is cytotoxic to cancer cells, via the formation of covalent DNA adducts and obstruction of DNA synthesis (Michalowsky and Jones, 1987;Juttermann et al, 1994). Meanwhile, lower, subtoxic doses of 5-aza-CdR have been shown to initiate reductions in 5-methylcytosine levels both globally (Creusot et al, 1982), as well as locally, in the CpGdense regulatory regions of a number of epigenetically silenced tumor suppressor genes, leading to their reactivation (Otterson et al, 1995;Herman et al, 1998;Bovenzi and Momparler, 2001;Oue et al, 2001;Koul et al, 2002). The non-cytotoxic, DNA hypomethylating effects of 5-aza-CdR have also been associated with differentiation and growth inhibition of tumor cells through cell-cycle arrest and/or apoptosis (Momparler et al, 1985;Bender et al, 1998;Hsi et al, 2005), enhancing interest in this drug as an anticancer agent.…”

Section: Introductionmentioning

confidence: 99%

5-Aza-2′-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation

et al. 2006

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The epigenetic silencing of tumor suppressor genes is a common event during carcinogenesis, and often involves aberrant DNA methylation and histone modification of gene regulatory regions, resulting in the formation of a transcriptionally repressive chromatin state. Two examples include the antimetastatic, tumor suppressor genes, desmocollin 3 (DSC3) and MASPIN, which are frequently silenced in this manner in human breast cancer. Treatment of the breast tumor cell lines MDA-MB-231 and UACC 1179 with 5-aza-2 0 -deoxycytidine (5-azaCdR) induced transcriptional reactivation of both genes in a dose-dependent manner. Importantly, DSC3 and MASPIN reactivation was closely and consistently linked with significant decreases in promoter H3 K9 di-methylation. Moreover, 5-aza-CdR treatment also resulted in global decreases in H3 K9 di-methylation, an effect that was linked to its ability to mediate dose-dependent, posttranscriptional decreases in the key enzyme responsible for this epigenetic modification, G9A. Finally, small interfering RNA (siRNA)-mediated knockdown of G9A and DNMT1 led to increased MASPIN expression in MDA-MB-231 cells, to levels that were supra-additive, verifying the importance of these enzymes in maintaining multiple layers of epigenetic repression in breast tumor cells. These results highlight an additional, complimentary mechanism of action for 5-aza-CdR in the reactivation of epigenetically silenced genes, in a manner that is independent of its effects on DNA methylation, further supporting an important role for H3 K9 methylation in the aberrant repression of tumor suppressor genes in human cancer.

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“…This conclusion is based on studies using both candidate gene approaches (Koul et al 2002, Smith-Sorensen et al 2002, Honorio et al 2003, Kempkensteffen et al 2006, Lind et al 2006, Brait et al 2012) and genome-wide approaches (Smiraglia et al 2002, Netto et al 2008, Wermann et al 2010, which have mainly focused on adult testicular GCTs (Table 2). Although some of these studies focused on a limited number of genes, microarray and genome-wide studies confirm that the methylation profile distinction between seminomas and non-seminomas is not restricted to just a few specific gene promoters (Lind et al 2007).…”

Section: Dna Methylation In Gctsmentioning

confidence: 99%

“…Two studies directly analysed the expression of eight genes that might be influenced by differential DNA methylation but failed to identify a convincing relationship (Koul et al 2002, Smith-Sorensen et al 2002. Indeed, the four genes found to be inactive in the majority of tumours that displayed promoter hypermethylation (MGMT, MLH1, RARB and RASSF1A) were either silent in most tumours regardless of methylation state or failed to be reactivated by 5-aza-2 0 -deoxyticidine treatment (a nucleoside analogue that causes demethylation of DNA).…”

Section: R55mentioning

confidence: 99%

“…Indeed, the four genes found to be inactive in the majority of tumours that displayed promoter hypermethylation (MGMT, MLH1, RARB and RASSF1A) were either silent in most tumours regardless of methylation state or failed to be reactivated by 5-aza-2 0 -deoxyticidine treatment (a nucleoside analogue that causes demethylation of DNA). A role for other gene regulatory factors was therefore suggested (Koul et al 2002, Smith-Sorensen et al 2002. Comparison of DNA methylation and gene expression data from matching samples allowed Jeyapalan et al (2011) to identify eight genes for which decreased expression in paediatric YSTs compared with seminomatous tumours correlated with CpG hypermethylation.…”

Section: R55mentioning

confidence: 99%

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DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

Cusack¹,

Scotting²

2013

Reproduction

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Germ cell tumours (GCTs) are a diverse group of neoplasms that can be histologically subclassified as either seminomatous or non-seminomatous. These two subtypes have distinct levels of differentiation and clinical characteristics, the non-seminomatous tumours being associated with poorer prognosis. In this article, we review how different patterns of aberrant DNA methylation relate to these subtypes. Aberrant DNA methylation is a hallmark of all human cancers, but particular subsets of cancers show unusually high frequencies of promoter region hypermethylation. Such a 'methylator phenotype' has been described in non-seminomatous tumours. We discuss the possible cause of distinct methylation profiles in GCTs and the potential of DNA methylation to provide new targets for therapy. We also consider how recent developments in our understanding of this epigenetic modification and the development of genome-wide technologies are shedding new light on the role of DNA methylation in cancer aetiology.Reproduction (2013) 146 R49-R60

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Untitled

Cited by 99 publications

References 27 publications

microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer

microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer

5-Aza-2′-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation

DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

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