Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer

Anshu Rastogi, Shyh Han Tan, Ahmed A. Mohamed, Yongmei Chen, Ying Hu, Gyorgy Petrovics, Taduru Sreenath, Jacob Kagan, Sudhir Srivastava, David G. McLeod, Isabell A. Sesterhenn, Shiv Srivastava, Albert Dobi*, Alagarsamy Srinivasan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


The fusion between ERG coding sequences and the TMPRSS2 promoter is the most prevalent in prostate cancer (CaP). The presence of two main types of TMPRSS2-ERG fusion transcripts in CaP specimens, Type I and Type II, prompted us to hypothesize that the cumulative actions of different ERG variants may impact CaP development/progression. Using TMPRSS2-ERG3 (Type I) and TMPRSS2-ERG8 (Type II) expression vectors, we determined that the TMPRSS2-ERG8 encoded protein is deficient in transcriptional regulation compared to TMPRSS2-ERG3. Co-transfection of vectors resulted in decreased transcriptional regulation compared to TMPRSS2-ERG3 alone, suggesting transdominance of ERG8. Expression of exogenous ERG8 protein resulted in a decrease in endogenous ERG3 protein levels in TMPRSS2-ERG positive VCaP cells, with a concomitant decrease in C-MYC. Further, we showed a physical association between ERG3 and ERG8 in live cells by the bimolecular fluorescence complementation assay, providing a basis for the observed effects. Inhibitory effects of TMPRSS2-ERG8 on TMPRSS2-ERG3 were also corroborated by gene expression data from human prostate cancers, which showed a positive correlation between C-MYC expression and TMPRSS2-ERG3/TMPRSS2-ERG8 ratio. We propose that an elevated TMPRSS2-ERG3/TMPRSS2-ERG8 ratio results in elevated C-MYC in CaP, providing a strong rationale for the biomarker and therapeutic utility of ERG splice variants, along with C-MYC.

Original languageEnglish
Pages (from-to)273-284
Number of pages12
JournalGenes and Cancer
Issue number7-8
StatePublished - 2014
Externally publishedYes


  • C-MYC
  • Dominant negative
  • ERG
  • Prostate cancer
  • Splice variants


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