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  ERG Induces Epigenetic Activation of Tudor Domain-Containing Protein 1 (TDRD1) in ERG Rearrangement-Positive Prostate Cancer

Kacprzyk, L. A., Laible, M., Andrasiuk, T., Brase, J. C., Börno, S., Falth, M., et al. (2013). ERG Induces Epigenetic Activation of Tudor Domain-Containing Protein 1 (TDRD1) in ERG Rearrangement-Positive Prostate Cancer. PLoS One, 8(3), e59976-e59976. doi:10.1371/journal.pone.0059976.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-060D-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-CE56-3
Genre: Journal Article

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2013
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2013 Kacprzyk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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 Creators:
Kacprzyk, L. A., Author
Laible, M., Author
Andrasiuk, T., Author
Brase, J. C., Author
Börno, S.1, Author              
Falth, M., Author
Kuner, R., Author
Lehrach, H.2, Author              
Schweiger, M. R.1, Author              
Sultmann, H., Author
Affiliations:
1Cancer Genomics (Michal-Ruth Schweiger), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479649              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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Free keywords: ewings-sarcoma translocation transcription factor erg gene-expression tmprss2-erg fusion piwi proteins small rnas ews gene germline cells family
 Abstract: Background: Overexpression of ERG transcription factor due to genomic ERG-rearrangements defines a separate molecular subtype of prostate tumors. One of the consequences of ERG accumulation is modulation of the cell's gene expression profile. Tudor domain-containing protein 1 gene (TDRD1) was reported to be differentially expressed between TMPRSS2:ERG-negative and TMPRSS2: ERG-positive prostate cancer. The aim of our study was to provide a mechanistic explanation for the transcriptional activation of TDRD1 in ERG rearrangement-positive prostate tumors. Methodology/Principal Findings: Gene expression measurements by real-time quantitative PCR revealed a remarkable co-expression of TDRD1 and ERG (r(2) = 0.77) but not ETV1 (r(2)< 0.01) in human prostate cancer in vivo. DNA methylation analysis by MeDIP-Seq and bisulfite sequencing showed that TDRD1 expression is inversely correlated with DNA methylation at the TDRD1 promoter in vitro and in vivo (p = -0.57). Accordingly, demethylation of the TDRD1 promoter in TMPRSS2:ERG-negative prostate cancer cells by DNA methyltransferase inhibitors resulted in TDRD1 induction. By manipulation of ERG dosage through gene silencing and forced expression we show that ERG governs loss of DNA methylation at the TDRD1 promoter-associated CpG island, leading to TDRD1 overexpression. Conclusions/Significance: We demonstrate that ERG is capable of disrupting a tissue-specific DNA methylation pattern at the TDRD1 promoter. As a result, TDRD1 becomes transcriptionally activated in TMPRSS2: ERG-positive prostate cancer. Given the prevalence of ERG fusions, TDRD1 overexpression is a common alteration in human prostate cancer which may be exploited for diagnostic or therapeutic procedures.

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Language(s): eng - English
 Dates: 2012-09-042013-02-192013-03-29
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1371/journal.pone.0059976
ISSN: 1932-6203
 Degree: -

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Title: PLoS One
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 8 (3) Sequence Number: - Start / End Page: e59976 - e59976 Identifier: ISSN: 1932-6203
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000277850