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Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer.


ABSTRACT: 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.

SUBMITTER: Rastogi A 

PROVIDER: S-EPMC4162137 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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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 reg  ...[more]

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