title: TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers.
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.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Ram-Shankar
authors.initials: RS
authors.lastname: Mani
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Iyer
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: J Chad
authors.initials: JC
authors.lastname: Brenner
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Aparna
authors.initials: A
authors.lastname: Ghosh
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
chemical_list: D017931:DNA Primers; C072312:ERG protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human