Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81.
ETS variant 1 (ETV1), also known as ETS-related protein 81, is overexpressed in prostate tumors, but whether and how this transcription factor affects tumorigenesis has remained elusive. Here, we show that ETV1 is primarily overexpressed in the most aggressive human prostate tumors. Transgenic ETV1 mice developed prostatic intraepithelial neoplasia as well as hyperplasia/neoplasia in seminal vesicles. Moreover, ETV1 cooperated with the androgen receptor (AR) to bind to the prostate-specific antigen enhancer and stimulate gene transcription. Consistent with its ability to physically interact with AR, ETV1 rendered an ETV1 binding site-driven reporter androgen inducible, and, on the other hand, ETV1 super-induced transcription from an AR binding site on androgen stimulation. In conclusion, our study substantiates that ETV1 overexpression is an underlying cause in the development of prostate and possibly also seminal vesicle cancer. Its interaction with and activation of AR provides a molecular mechanism on how ETV1 exerts its deleterious function. Thus, inhibiting ETV1 or blocking its interaction with AR may represent novel strategies in prostate cancer therapy.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Sook
S
Shin
Tae-Dong
TD
Kim
Fang
F
Jin
Jan M
JM
van Deursen
Scott M
SM
Dehm
Donald J
DJ
Tindall
Joseph P
JP
Grande
Jan-Marie
JM
Munz
George
G
Vasmatzis
Ralf
R
Janknecht
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D007834:Lasers; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D042282:Microdissection; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection
C410798:AR protein, human; D000728:Androgens; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D014157:Transcription Factors; D008156:Luciferases; D017430:Prostate-Specific Antigen