Shin Sook, Kim Tae-Dong, Jin Fang, van Deursen Jan M, Dehm Scott M, Tindall Donald J, Grande Joseph P, Munz Jan-Marie, Vasmatzis George, Janknecht Ralf
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Cancer Res. 2009 Oct 15;69(20):8102-10. doi: 10.1158/0008-5472.CAN-09-0941. Epub 2009 Sep 29.
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.
ETS变异体1（ETV1），也被称为ETS相关蛋白81，在前列腺肿瘤中过度表达，但这种转录因子是否以及如何影响肿瘤发生仍不清楚。在此，我们表明ETV1主要在最具侵袭性的人类前列腺肿瘤中过度表达。转基因ETV1小鼠发生了前列腺上皮内瘤变以及精囊增生/瘤变。此外，ETV1与雄激素受体（AR）协同作用，结合到前列腺特异性抗原增强子上并刺激基因转录。与其与AR进行物理相互作用的能力一致，ETV1使一个由ETV1结合位点驱动的报告基因受雄激素诱导，另一方面，ETV1在雄激素刺激下从AR结合位点超诱导转录。总之，我们的研究证实ETV1过度表达是前列腺癌以及可能还有精囊癌发生的一个潜在原因。它与AR的相互作用及激活为ETV1如何发挥其有害功能提供了一种分子机制。因此，抑制ETV1或阻断其与AR的相互作用可能代表前列腺癌治疗的新策略。
