title: YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion.
abstract: BACKGROUND
  Genomic rearrangements involving the ETS family of transcription factors occur in 40-70% of prostate cancer cases. ERG and ETV1 are the most common ETS members observed in these genetic alterations. The high prevalence of these rearrangements and their biological significance represents a novel therapeutic target for the treatment of prostate cancer.
  
  
  RESULTS
  We recently reported the development of YK-4-279, a small molecule inhibitor of EWS-FLI1 oncoprotein in Ewing's Sarcoma. Since ERG and ETV1 belong to the same class of ETS factors as FLI1, we tested the ability of YK-4-279 to inhibit biological functions of ERG and ETV1 proteins in prostate cancer. YK-4-279 inhibited ERG and ETV1 mediated transcriptional activity in a luciferase assay. YK-4-279 also decreased ERG and ETV1 downstream target mRNA and protein expression in ETV1-fusion positive LNCaP and ERG fusion positive VCaP cells. YK-4-279 reduced the motility of LNCaP cells in a scratch assay and the invasive phenotype of both LNCaP and VCaP cells in a HUVEC invasion assay. Fusion-negative PC3 cells were unresponsive to YK-4-279. SiRNA mediated ERG knockdown in VCaP cells resulted in a loss of drug responsiveness. Concurrently, transient ERG expression in PC-3 cells resulted in increased invasive potential, which was reduced by YK-4-279.
  
  
  CONCLUSIONS
  These data demonstrate that YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion. Therefore, YK-4-279 may have an impact on metastasis in prostate cancer and it may be further evaluated for its clinical applications in prostate cancer in addition to Ewing's sarcoma.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America.
authors.forename: Said
authors.initials: S
authors.lastname: Rahim
authors.forename: Elspeth M
authors.initials: EM
authors.lastname: Beauchamp
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C072312:ERG protein, human; C095239:ETV1 protein, human; D007211:Indoles; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C562345:YK 4-279