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

Ram Shankar Mani, Matthew K. Iyer, Qi Cao, J. Chad Brenner, Lei Wang, Aparna Ghosh, Xuhong Cao, Robert J. Lonigro, Scott A. Tomlins, Sooryanarayana Varambally, Arul M. Chinnaiyan

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5387-5392
Number of pages6
JournalCancer research
Volume71
Issue number16
DOIs
StatePublished - Aug 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mani, R. S., Iyer, M. K., Cao, Q., Brenner, J. C., Wang, L., Ghosh, A., Cao, X., Lonigro, R. J., Tomlins, S. A., Varambally, S., & Chinnaiyan, A. M. (2011). TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers. Cancer research, 71(16), 5387-5392. https://doi.org/10.1158/0008-5472.CAN-11-0876