title: 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 prostate cancer phenotypes. Previously, we and others have shown that the transcription factor ERG regulates CXCR4 expression in prostate cancer cells and that androgens modulate CXCR4 expression via increasing ERG expression. Herein, the molecular mechanisms of ERG-mediated CXCR4 promoter activation, phosphorylation of ERG by intracellular kinases and subsequent CXCR4 expression, as well as the status of ERG and CXCR4 in human prostate cancer specimens were investigated. Using multiple molecular strategies, it was demonstrated that (i) ERG expressed in TMPRSS2-ERG fusion positive VCaP cells selectively binds to specific ERG/Ets bindings sites in the CXCR4 promoter; (ii) distal binding sites mediate promoter activation; (iii) exogenously expressed ERG promotes CXCR4 expression; (iv) ERG is phosphorylated at Serine-81 and -215, by both IKK and Akt kinases, and Akt mediates CXCR4 expression; (v) ERG-induced CXCR4 drives CXCL12-dependent adhesion to fibronectin; and (vi) ERG and CXCR4 were coexpressed in human prostate cancer tissue, consistent with ERG-mediated transcriptional activation of CXCR4. These data demonstrate that ERG activates CXCR4 expression by binding to specific ERG/Ets responsive elements and via intracellular kinases that phosphorylate ERG at discrete serine residues.
  
  
  CONCLUSIONS
  These findings 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.
authors.affiliation: Departments of Urology and Pathology, Wayne State University School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI 48201. schinni@med.wayne.edu.
authors.forename: Rajareddy
authors.initials: R
authors.lastname: Singareddy
authors.forename: Louie
authors.initials: L
authors.lastname: Semaan
authors.forename: M Katie
authors.initials: MK
authors.lastname: Conley-Lacomb
authors.forename: Jason
authors.initials: J
authors.lastname: St John
authors.forename: Katelyn
authors.initials: K
authors.lastname: Powell
authors.forename: Matthew
authors.initials: M
authors.lastname: Iyer
authors.forename: Daryn
authors.initials: D
authors.lastname: Smith
authors.forename: Lance K
authors.initials: LK
authors.lastname: Heilbrun
authors.forename: Dongping
authors.initials: D
authors.lastname: Shi
authors.forename: Wael
authors.initials: W
authors.lastname: Sakr
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cher
authors.forename: Sreenivasa R
authors.initials: SR
authors.lastname: Chinni
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D059016:Tumor Microenvironment
chemical_list: C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D019718:Receptors, CXCR4; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human
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