The Role ERG and CXCR4 in Prostate Cancer Progression

Abstract

Abstract : TMPRSS2-ERG fusion transcripts have been shown to be expressed in a majority of prostate cancer (PC) patients due to chromosomal translocations or deletions involving the TMPRSS2 gene promoter and the ERG gene coding sequence. These alterations cause androgen dependent ERG transcription factor expression in PC patients. We and others have shown that chemokine receptor CXCR4 expression is upregulated in PC tumor cells and its ligand, CXCL12, is expressed in bone stromal cells. The CXCL12/CXCR4 axis functions in PC progression to enhance invasion and metastasis. To address the regulation of CXCR4 expression, we identified several putative ERG consensus binding sites in the promoter region of CXCR4. We hypothesized that androgen dependent regulation of the ERG transcription factor could induce CXCR4 expression in PC cells. Results of the current study show that (a) ERG protein expressed from TMPRSS2-ERG fusion gene binds selective ERG binding elements in CXCR4 promoter in VCaP cells; (b) Upstream ERG binding sites in CXCR4 promoter are active in ERG induced CXCR4 promoter activation; (c) R1881 induced ERG gene mediates CXCR4 expression in androgen responsive prostate cancer cells. These findings demonstrate biochemical interaction between ERG factor and CXCR4 gene promoter and link these activities with TMPRSS2-ERG translocations and enhanced metastasis of tumor cells via CXCR4 function in PC cells.