title: 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.
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Anshu
authors.initials: A
authors.lastname: Rastogi
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Shyh-Han
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Mohamed
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Petrovics
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Taduru
authors.initials: T
authors.lastname: Sreenath
authors.affiliation: Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA;
authors.forename: Jacob
authors.initials: J
authors.lastname: Kagan
authors.affiliation: Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA;
authors.forename: Sudhir
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; ; Urology Service, Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA;
authors.forename: David G
authors.initials: DG
authors.lastname: McLeod
authors.affiliation: The Joint Pathology Center; Silver Spring, MD, USA.
authors.forename: Isabell A
authors.initials: IA
authors.lastname: Sesterhenn
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Shiv
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Albert
authors.initials: A
authors.lastname: Dobi
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
authors.forename: Alagarsamy
authors.initials: A
authors.lastname: Srinivasan
keywords: C-MYC; Dominant negative; ERG; Prostate cancer; Splice variants