Molecular Subtyping of Primary Prostate Cancer Reveals Specific and Shared Target Genes of Different ETS Rearrangements

Abstract

This work aimed to evaluate whether ETS transcription factors frequently involved in rearrangements in prostate carcinomas (PCa), namely ERG and ETV1, regulate specific or shared target genes. We performed differential expression analysis on nine normal prostate tissues and 50 PCa enriched for different ETS rearrangements using exon-level expression microarrays, followed by in vitro validation using cell line models. We found specific deregulation of 57 genes in ERG-positive PCa and 15 genes in ETV1-positive PCa, whereas deregulation of 27 genes was shared in both tumor subtypes. We further showed that the expression of seven tumor-associated ERG target genes (PLA1A, CACNA1D, ATP8A2, HLA-DMB, PDE3B, TDRD1, and TMBIM1) and two tumor-associated ETV1 target genes (FKBP10 and GLYATL2) was significantly affected by specific ETS silencing in VCaP and LNCaP cell line models, respectively, whereas the expression of three candidate ERG and ETV1 shared targets (GRPR, KCNH8, and TMEM45B) was significantly affected by silencing of either ETS. Interestingly, we demonstrate that the expression of TDRD1, the topmost overexpressed gene of our list of ERG-specific candidate targets, is inversely correlated with the methylation levels of a CpG island found at -66 bp of the transcription start site in PCa and that TDRD1 expression is regulated by direct binding of ERG to the CpG island in VCaP cells. We conclude that ETS transcription factors regulate specific and shared target genes and that TDRD1, FKBP10, and GRPR are promising therapeutic targets and can serve as diagnostic markers for molecular subtypes of PCa harboring specific fusion gene rearrangements.

ETS fusion genes in prostate cancer

“…They might be indirectly regulated by ERG or they might represent a common prostate cell type in which TMPRSS2-ERG fusion occurred. Recently, TDRD1 has been identified as the first directly ERG-regulated gene (Paulo et al 2012. The mechanism of expression of other ERG-associated genes remains to be investigated.…”

“…As an example, although ERG inhibits PSA expression, ETVI seems to stimulate PSA expression (Shin et al 2009, Yu et al 2010. Paulo et al (2012) recently suggested that there are both specific and shared targets of ETV1 and ERG. Applying unsupervised clustering of mRNA from primary clinical samples, we observed that ETV1-positive and ERG-positive tumor samples clustered separately , Gasi Tandefelt et al 2013.…”

In vitro model systems to study androgen receptor signaling in prostate cancer

“…In addition, these cell lines also harbor a TMPRSS2:ERG gene fusion and thus are frequently used to investigate the functional significance of the genetic rearrangement involving ERG, a member of the ETS family of transcription factors, which is the most common genetic aberration in PCa identified to date ( Fig. 2; Tomlins et al 2008, Paulo et al 2012. In addition to wild-type AR, VCaPs also express several alternatively spliced AR isoforms in response to castration or androgen deprivation with one variant lacking the LBD (Dehm et al 2008, Watson et al 2010, which like other recently identified AR variants appears to act as a constitutively active, ligand-independent transcription factor to support AR reactivation in CR-PCa ( Fig.…”

FK506 Binding Protein 10 Is Overexpressed and Promotes Renal Cell Carcinoma

“…Different from all the other family proteins, FKBP10 contains 4 PPIase domains [20,21] . FKBP10 has been implicated in ovarian cancer [17,22] , colorectal cancer [23] , KRAS-induced lung cancer [18] , prostate cancer [24], and leukemia [25] .…”