yk-4-279 inhibits erg and etv1 mediated prostate cancer cell invasionyk - 4 - 279抑制erg和前列腺癌etv1介导细胞入侵.pdfVIP

YK-4-279 Inhibits ERG and ETV1 Mediated Prostate Cancer Cell Invasion ¨ Said Rahim, Elspeth M. Beauchamp, Yali Kong, Milton L. Brown, Jeffrey A. Toretsky, Aykut Uren* Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America 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. Methods and Findings: 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. Conclusion