ERG induces epigenetic activation of Tudor domain-containing protein 1 (TDRD1) in ERG rearrangement-positive prostate cancer

PLoS One. 2013;8(3):e59976. doi: 10.1371/journal.pone.0059976. Epub 2013 Mar 29.

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 (ρ = -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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • DNA Methylation
  • Epigenomics
  • Humans
  • In Vitro Techniques
  • Male
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcriptional Regulator ERG

Substances

  • Carrier Proteins
  • ERG protein, human
  • TDRD1 protein, human
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Grant support

This work was supported by the German Federal Ministry of Education and Research (http://www.bmbf.de/en/) in the framework of the Program for Medical Genome Research (NGFNplus; IG-Prostate Cancer, 01GS0890 and 01GS0891; IG-Mutanom, 01GS08107; Intestinal Modifier, 01GS08111) as well as the Helmholtz International Graduate School for Cancer Research of the DKFZ ((www.dkfz.de/phd/)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.