TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers

Academic Article

Abstract

  • Recurrent gene fusions involving ETS family genes are a distinguishing feature of human prostate cancers, with TMPRSS2-ERG fusions representing the most common subtype. The TMPRSS2-ERG fusion transcript and its splice variants are well characterized in prostate cancers; however, not much is known about the levels and regulation of wild-type ERG. By employing an integrative approach, we show that the TMPRSS2-ERG gene fusion product binds to the ERG locus and drives the overexpression of wild-type ERG in prostate cancers. Knockdown of TMPRSS2-ERG in VCaP cells resulted in the downregulation of wild-type ERG transcription, whereas stable overexpression of TMPRSS2-ERG in the gene fusion-negative PC3 cells was associated with the upregulation of wild-type ERG transcript. Further, androgen signaling-mediated upregulation of TMPRSS2-ERG resulted in the concomitant upregulation of wild-type ERG transcription in VCaP cells. The loss of wild-type ERG expression was associated with a decrease in the invasive potential of VCaP cells. Importantly, 38% of clinically localized prostate cancers and 27% of metastatic prostate cancers harboring the TMPRSS2-ERG gene fusions exhibited overexpression of wild-type ERG. Taken together, these results provide novel insights into the regulation of ERG in human prostate cancers. ©2011 AACR.
  • Published In

  • Cancer Research  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 15329393
  • Author List

  • Mani RS; Iyer MK; Cao Q; Brenner JC; Wang L; Ghosh A; Cao X; Lonigro RJ; Tomlins SA; Varambally S
  • Start Page

  • 5387
  • End Page

  • 5392
  • Volume

  • 71
  • Issue

  • 16