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Background  In normal prostate epithelium the  TMPRSS2  gene encoding a type II serine protease is directly regulated by male hormones through the androgen receptor. In prostate cancer  ERG  protooncogene frequently gains hormonal control by seizing gene regulatory elements of  TMPRSS2  through genomic fusion events. Although, the androgenic activation of  TMPRSS2  gene has been established, little is known about other elements that may interact with  TMPRSS2  promoter sequences to modulate  ERG  expression in  TMPRSS2-ERG  gene fusion context.    Methods  Comparative genomic analyses of the  TMPRSS2  promoter upstream sequences and pathway analyses were performed by the Genomatix Software.  NKX3.1  and  ERG  genes expressions were evaluated by immunoblot or by quantitative Real-Time PCR (qRT-PCR) assays in response to siRNA knockdown or heterologous expression. QRT-PCR assay was used for monitoring the gene expression levels of NKX3.1-regulated genes. Transcriptional regulatory function of NKX3.1 was assessed by luciferase assay. Recruitment of NKX3.1 to its cognate elements was monitored by Chromatin Immunoprecipitation assay.    Results  Comparative analysis of the  TMPRSS2  promoter upstream sequences among different species revealed the conservation of binding sites for the androgen inducible  NKX3.1  tumor suppressor. Defects of  NKX3.1 , such as, allelic loss, haploinsufficiency, attenuated expression or decreased protein stability represent established pathways in prostate tumorigenesis. We found that NKX3.1 directly binds to  TMPRSS2  upstream sequences and negatively regulates the expression of the  ERG  protooncogene through the  TMPRSS2-ERG  gene fusion.    Conclusions  These observations imply that the frequently noted loss-of-function of NKX3.1 cooperates with the activation of  TMPRSS2-ERG  fusions in prostate tumorigenesis.

Loss of the NKX3.1 tumorsuppressor promotes the TMPRSS2-ERG fusion gene expression in prostate cancer