Transcriptional Regulation of CXCR4 in Prostate Cancer: Significance of TMPRSS2-ERG Fusions

Abstract

CXCR4 is a chemokine receptor that mediates invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive phenotypes of prostate cancer. Previously, we and others have shown that the ERG transcription factor regulates CXCR4 expression in prostate cancer cells. We further showed that androgens regulate CXCR4 expression via increasing ERG transcription factor expression. Herein, we investigated molecular mechanisms of ERG-mediated CXCR4 promoter activation, phosphorylation of ERG by intracellular kinases and subsequent CXCR4 expression, as well as expression of ERG and CXCR4 in human prostate tumor tissues. Using multiple molecular strategies, we demonstrate that: (a) ERG expressed in TMPRSS2-ERG fusion positive VCaP cells selectively binds with specific ERG/Ets bindings sites in the CXCR4 promoter; (b) distal binding sites mediate promoter activation; (c) exogenously expressed ERG promotes CXCR4 expression; (d) ERG is phosphorylated at Serine 81 and 215, both IKK and Akt kinases induce serine phosphorylation, and Akt mediates CXCR4 expression; (e) ERG-induced CXCR4 drives CXCL12-dependent adhesion to fibronectin; (f) ERG and CXCR4 were co-expressed in human prostate tumor tissues, consistent with ERG-mediated transcriptional activation of CXCR4. These data demonstrates that ERG factor activates CXCR4 expression by binding to the specific ERG/Ets responsive elements and intracellular kinases phosphorylate at ERG at serine residues to induce CXCR4 expression. These findings may provide a mechanistic link between TMPRSS2-ERG translocations and intracellular kinase mediated phosphorylation of ERG on enhanced metastasis of tumor cells via CXCR4 expression and function in prostate cancer cells.

ERG-Mediated Cell Invasion: A Link between Development and Tumorigenesis

“…Recently, it was demonstrated that ERK2 phosphorylates serine 215 of ERG isoform 1 [24]. Although serine 215 is not localized in the ETS domain, this phosphorylation is essential for ERG binding to DNA, expression of its downstream target chemokine receptor CXCR4, and the aggressive behavior of prostate cancer cells [6,24,25,26]. Other posttranslational modifications of ERG and their roles in protein activity or localization remain to be identified, which could shed light on the molecular mechanism of ERG-mediated transcription in prostate cancer.…”

“…In ERG-positive cancers, ERG binds to the promoter of CXCR4 to activate transcription [25,26]. Several studies have demonstrated functional outcomes of ERG-mediated CXCR4 overexpression, including increased cell migration [6] and metastasis to bone [25].…”

The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells

“…Tumours in which the loss of PTEN protein is observed at biopsy are more likely to have higher Gleason scores (15). Thus both ERG and PTEN are especially important players in prostate cancer; but the extent to which they might interact is not yet clear (16,17). Given the presence several potential ERG binding sites in the PTEN promoter, we sought to determine whether or not the transcription factor ERG might regulate PTEN expression directly.…”

Discovery and Classification of Fusion Transcripts in Prostate Cancer and Normal Prostate Tissue

“…Such complexity may contribute to the variation of the analyses. ERG is a transcription factor that is activated by phosphorylation at its serine residues 81 and 215 by AKT kinase 70 ( Figure 2). Presumably, the activated ERG induces the expression of several critical proteins that mediates cell growth 71 and invasion.…”

“…Presumably, the activated ERG induces the expression of several critical proteins that mediates cell growth 71 and invasion. 70,72 CXCR4 and MMP9 are of particular interest because they were well documented as direct mediators of adhesion and invasion, respectively. Increased levels of CXCR4 and MMP9 may co-operate to enhance the invasion of prostate cancer.…”