Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer
Anshu Rastogi1, Shyh-Han Tan1, Ahmed A. Mohamed1, Yongmei Chen1, Ying Hu1, Gyorgy Petrovics1, Taduru Sreenath1, Jacob Kagan2, Sudhir Srivastava2, David G. McLeod1,3, Isabell A. Sesterhenn4, Shiv Srivastava1 , Albert Dobi1, Alagarsamy Srinivasan1
1 Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
2 Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA;
3 Urology Service, Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA;
4 The Joint Pathology Center; Silver Spring, MD, USA.
Correspondence:
Albert Dobi, email:
Correspondence:
Alagarsamy Srinivasan, email:
Keywords: ERG, Splice variants, Prostate cancer, Dominant negative, C-MYC
Received: July 1, 2014 Accepted: August 8, 2014 Published: August 9, 2014
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.
