Logan Ian R, Gaughan Luke, McCracken Stuart R C, Sapountzi Vasileia, Leung Hing Y, Robson Craig N
University of Newcastle Upon Tyne, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, United Kingdom.
Mol Cell Biol. 2006 Sep;26(17):6502-10. doi: 10.1128/MCB.00147-06.
The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer.
雄激素受体（AR）是一种激素依赖性转录因子，在人类前列腺癌发生过程中起关键作用。AR对雄激素反应性基因的最佳转录调控可能需要多种共调节蛋白之间的复杂相互作用。我们之前已经表明，AR共调节因子TIP60可以与人PIRH2（hPIRH2）相互作用。在本研究中，我们揭示了hPIRH2在AR信号传导中的重要新功能：（i）hPIRH2与AR相互作用，并通过动态募集到前列腺特异性抗原（PSA）基因中的雄激素反应元件来增强AR介导的转录；（ii）hPIRH2与AR共抑制因子HDAC1相互作用，导致HDAC1蛋白水平降低并抑制转录抑制；（iii）最佳PSA表达需要hPIRH2；（iv）hPIRH2参与前列腺癌细胞增殖。此外，在82例切除的前列腺癌中有73例（89%）检测到hPIRH2蛋白过表达，hPIRH2表达增加与侵袭性疾病之间存在强烈相关性，高Gleason总分和转移性疾病的存在表明了这一点（分别为P = <0.0001和0.0004）。总体而言，我们的数据表明hPIRH2是AR功能的关键调节因子，为侵袭性人类前列腺癌的靶向治疗开辟了新方向。
