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Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation.

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Title: Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation.
Authors: Benešová, M
Trejbalová, K
Kučerová, D
Vernerová, Z
Hron, T
Szabó, A
Amouroux, R
Klézl, P
Hajkova, P
Hejnar, J
Item Type: Journal Article
Abstract: Germ cell tumors and particularly seminomas reflect the epigenomic features of their parental primordial germ cells, including genomic DNA hypomethylation and expression of pluripotent cell markers. Because the DNA hypomethylation might be a result of TET dioxygenase activity, we examined expression of TET1-3 enzymes and the level of their product, 5-hydroxymethylcytosine, in a panel of histologically characterized seminomas and non-seminomatous germ cell tumors. Expression of TET dioxygenase mRNAs was quantified by real-time PCR. TET1 expression and the level of 5-hydroxymethylcytosine were examined immunohistochemically. Quantitative assessment of 5-methylcytosine and 5-hydroxymethylcytosine levels was done by the liquid chromatography-mass spectroscopy technique. We found highly increased expression of TET1 dioxygenase in most seminomas and strong TET1 staining in seminoma cells. Isocitrate dehydrogenase 1 and 2 mutations were not detected, suggesting the enzymatic activity of TET1. The levels of 5-methylcytosine and 5-hydroxymethylcytosine in seminomas were found decreased in comparison to non-seminomatous germ cell tumors and healthy testicular tissue. We propose that TET1 expression should be studied as a potential marker of seminomas and mixed germ cell tumors and we suggest that elevated expression of TET dioxygenase enzymes is associated with the maintenance of low DNA methylation levels in seminomas. This "anti-methylator" phenotype of seminomas is in contrast to the CpG island methylator phenotype observed in a fraction of tumors of various types.
Issue Date: 20-Feb-2017
Date of Acceptance: 16-Feb-2017
URI: http://hdl.handle.net/10044/1/45711
DOI: https://dx.doi.org/10.1002/mc.22638
ISSN: 1098-2744
Publisher: Wiley
Start Page: 1837
End Page: 1850
Journal / Book Title: Molecular Carcinogenesis
Volume: 56
Issue: 8
Copyright Statement: This is the peer reviewed version of the following article: Benešová M, Trejbalová K, Kučerová D, et al. Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation. Molecular Carcinogenesis. 2017; 56:1837–1850. , which has been published in final form at https://doi.org/10.1002/mc.22638.  This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Sponsor/Funder: EMBO
Commission of the European Communities
Funder's Grant Number: EMBO YIP
648879
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
5-hydroxymethylcytosine
5-methylcytosine
germ cell tumor
seminoma
TET1
GERM-CELL TUMORS
CARCINOMA IN-SITU
GENE-EXPRESSION
COLORECTAL-CANCER
TESTICULAR CANCER
MAMMALIAN DNA
5-METHYLCYTOSINE
GENOME
5-HYDROXYMETHYLCYTOSINE
MUTATIONS
5-Methylcytosine
Adult
DNA Methylation
DNA-Binding Proteins
Dioxygenases
Gene Expression Regulation, Neoplastic
Humans
Male
Mixed Function Oxygenases
Proto-Oncogene Proteins
Seminoma
Testicular Neoplasms
Testis
Up-Regulation
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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