Abstract
BackgroundOverexpression 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 FindingsGene expression measurements by real-time quantitative PCR revealed a remarkable co-expression of TDRD1 and ERG (r2 = 0.77) but not ETV1 (r2<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/SignificanceWe 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.
Highlights
Half of human prostate cancer cases identified by PSA-screening harbor genomic rearrangements in which androgenresponsive regulatory elements are juxtaposed to genes coding for transcription factors of the ETS family [1,2,3]
We performed a correlation analysis on the data from 93 prostate tissue samples (46 benign, 30 TMPRSS2:ERG-negative, 17 TMPRSS2:ERG-positive prostate tumors) and found that mRNA levels of ERG and Tudor domain-containing protein 1 gene (TDRD1) measured by Human Exon 1.0 ST Array are remarkably correlated across all samples (r2 = 0.84), suggesting a mechanistic link between the two genes
TDRD1 was not coexpressed with ETV1 (r2 = 0.05) which is an ETS transcription factor found to be sporadically rearranged in prostate cancer
Summary
Half of human prostate cancer cases identified by PSA-screening harbor genomic rearrangements in which androgenresponsive regulatory elements are juxtaposed to genes coding for transcription factors of the ETS family [1,2,3]. ETS genes become coupled to androgen receptor (AR) signaling and are overexpressed in fusion-positive prostate tumors [4,5,6]. The most prevalent of these genomic rearrangements, the TMPRSS2:ERG gene fusion, leads to a strong overexpression of the ERG transcription factor which is otherwise absent in cells of the prostate epithelium [7]; under physiological conditions ERG displays a tissuerestricted expression pattern and is transcribed in the hematopoietic linage [8] and endothelial cells [9]. Overexpression of ERG transcription factor due to genomic ERG-rearrangements defines a separate molecular subtype of prostate tumors. The aim of our study was to provide a mechanistic explanation for the transcriptional activation of TDRD1 in ERG rearrangement-positive prostate tumors
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