Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements

Neoplasia. 2012 Jul;14(7):600-11. doi: 10.1593/neo.12600.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cluster Analysis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Oncogene Fusion*
  • Prostatic Neoplasms / classification
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-ets / genetics*
  • Proto-Oncogene Proteins c-ets / metabolism
  • RNA Interference
  • Reproducibility of Results
  • Tacrolimus Binding Proteins / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Regulator ERG

Substances

  • DNA-Binding Proteins
  • ERG protein, human
  • ETV1 protein, human
  • Proto-Oncogene Proteins c-ets
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Regulator ERG
  • Tacrolimus Binding Proteins
  • FKBP10 protein, human