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SARAH PATRICE JUSTVIG
The Effect of Small Molecule Inhibitor YK-4-279 on Activity of Transcription
Factors in Prostate Cancer
Dr. Heidi Elmendorf, Department of Biology, Georgetown University; Dr. Aykut Üren
and Saïd Rahim, Department of Oncology, Department of Biochemistry and Molecular &
Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University
Medical Center
The ETS family of transcription factors is implicated in 40-70% of prostate
cancers, including the most penetrating forms. Transcriptional regulator proteins ERG
and ETV1 are members of the ETS family. EWS/FLI1, an oncogenic, chimeric fusion
protein of Ewing’s sarcoma, shares with ERG and ETV1 identification as a Class I ETS
factor. The three are more than 60% identical and 80% homologous in their amino acid
sequences. YK-4-279 has been identified as a small molecule inhibitor of EWS/FLI1
oncoprotein in Ewing’s sarcoma. Given the strong similarity between EWS/FLI1 in
Ewing’s sarcoma and ERG and ETV1 in prostate cancer, we hypothesized that YK-4-279
may inhibit ERG and ETV1 transcriptional activity.
In an effort to determine the effect of YK-4-279 on ERG/ETV1 function with
transcriptional activity as a readout, we chose ERG/ETV1-regulated target genes,
optimized primer pairs, and performed qPCR to study relative gene expression of YK-4279 and DMSO groups both in vitro and in vivo. We utilized the human LNCaP cell line
and subcutaneous xenografts, namely eight SCID mice, respectively. We found that YK4-279 significantly inhibited ERG/ETV1 function in MMP-7, FKBP10, and GLYATL2
target genes but that YK-4-279’s inhibition of ERG/ETV1 function in MMP-13 in vitro
did not translate to the in vivo model. We are now extending our focus from a
transcriptional level to a translational level through Western blotting, looking at YK-4279’s ability to affect protein levels.
References
Erkizan, H.V., Kong, Y., Merchant, M., Schlottmann, S., Barber-Rotenberg, J.S., Yuan,
L., Abaan, O.D., Chou, T., Dakshanamurthy, S., Brown, M.L., Üren, A., and
Toretsky, J.A. (2009) Nat. Med. 15(7):750-757.
Rahim, S., Beauchamp, E.M., Kong, Y., Brown, M.L., Toretsky, J.A., and Üren, A.
(2011) YK-4-279 Inhibits ERG and ETV1 Mediated Prostate Cancer Cell
Invasion. PLOS ONE. 6(4):1-8.