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Updated: Jun 2, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion
Said Rahim1, Elspeth M Beauchamp, Yali Kong
1Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America.
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:
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.
Insights
A novel drug, YK-4-279, effectively inhibits ETS gene fusions (ERG, ETV1) in prostate cancer cells. This inhibition reduces cancer cell motility and invasion, suggesting potential for treating metastatic prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genomic rearrangements of ETS transcription factors, particularly ERG and ETV1, are prevalent in prostate cancer (40-70%).
- These ETS gene alterations are biologically significant and represent a promising therapeutic target for prostate cancer treatment.
Purpose of the Study:
- To investigate the efficacy of YK-4-279, a small molecule inhibitor, against ERG and ETV1 proteins in prostate cancer.
- To evaluate the impact of YK-4-279 on the biological functions of ERG and ETV1, including transcriptional activity, cell motility, and invasion.
Main Methods:
- Utilized luciferase assays to assess YK-4-279's inhibition of ERG/ETV1-mediated transcriptional activity.
- Measured downstream mRNA and protein expression changes in response to YK-4-279 in fusion-positive prostate cancer cell lines (LNCaP, VCaP).
- Assessed cell motility and invasion using scratch and HUVEC invasion assays, respectively; employed siRNA and transient expression for further validation.
Main Results:
- YK-4-279 significantly inhibited ERG and ETV1 transcriptional activity and downstream target expression.
- The drug reduced the motility and invasive potential of prostate cancer cells harboring ERG or ETV1 fusions.
- Fusion-negative cells (PC3) were unresponsive, and ERG knockdown/expression modulated drug response and invasiveness.
Conclusions:
- YK-4-279 demonstrates potent inhibition of ERG and ETV1 biological activity in prostate cancer cells.
- These findings suggest YK-4-279 has potential to impact prostate cancer metastasis.
- Further clinical evaluation of YK-4-279 for prostate cancer treatment is warranted.
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