Hu Yueh-Chiang, Yeh Shuyuan, Yeh Shauh-Der, Sampson Erik R, Huang Jiaoti, Li Peng, Hsu Cheng-Lung, Ting Huei-Ju, Lin Hui-Kuan, Wang Liang, Kim Eungseok, Ni Jing, Chang Chawnshang
George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester, Rochester, New York 14642, USA.
J Biol Chem. 2004 Aug 6;279(32):33438-46. doi: 10.1074/jbc.M401781200. Epub 2004 May 27.
Androgen receptor (AR)-associated coregulator 70 (ARA70) was the first identified AR coregulator. However, its molecular mechanism and biological relevance to prostate cancer remain unclear. Here we show that ARA70 interacts with and promotes AR activity via the consensus FXXLF motif within the ARA70-N2 domain (amino acids 176-401). However, it does not promote AR activity via the classic LXXLL motif located at amino acids 92-96, although this classic LXXLL motif is important for ARA70 to interact with other receptors, such as PPARgamma. The molecular mechanisms by which ARA70 enhances AR transactivation involve the increase of AR expression, protein stability, and nuclear translocation. Furthermore, ARA70 protein is more frequently detected in prostate cancer specimens (91.74%) than in benign tissues (64.64%, p < 0.0001). ARA70 expression is also increased in high-grade prostate cancer tissues as well as the hormone-refractory LNCaP xenografts and prostate cancer cell lines. Because ARA70 can promote the antiandrogen hydroxyflutamide (HF)-enhanced AR transactivation, the increased ARA70 expression in hormone-refractory prostate tumors may confer the development of HF withdrawal syndrome, commonly diagnosed in patients with the later stages of prostate cancer. Because ARA70-N2 containing the AR-interacting FXXLF motif without coactivation function can suppress HF-enhanced AR transactivation in the hormone-refractory LNCaP cells, using the ARA70-N2 inhibitory peptide at the hormone refractory stage to battle the HF withdrawal syndrome may become an alternative strategy to treat prostate cancer.
雄激素受体（AR）相关共调节因子70（ARA70）是首个被鉴定出的AR共调节因子。然而，其分子机制以及与前列腺癌的生物学相关性仍不清楚。在此我们表明，ARA70通过ARA70-N2结构域（氨基酸176 - 401）内的共有FXXLF基序与AR相互作用并促进AR活性。然而，它并不通过位于氨基酸92 - 96处的经典LXXLL基序促进AR活性，尽管这个经典LXXLL基序对于ARA70与其他受体如PPARγ相互作用很重要。ARA70增强AR反式激活的分子机制涉及AR表达的增加、蛋白质稳定性和核转位。此外，在前列腺癌标本中（91.74%）比在良性组织中（64.64%，p < 0.0001）更频繁地检测到ARA70蛋白。在高级别前列腺癌组织以及激素难治性LNCaP异种移植物和前列腺癌细胞系中，ARA70表达也增加。由于ARA70可促进抗雄激素羟基氟他胺（HF）增强的AR反式激活，激素难治性前列腺肿瘤中ARA70表达的增加可能导致HF撤药综合征的发生，这在前列腺癌晚期患者中很常见。因为不含共激活功能但含有与AR相互作用的FXXLF基序的ARA70-N2可抑制激素难治性LNCaP细胞中HF增强的AR反式激活，在激素难治阶段使用ARA70-N2抑制肽来对抗HF撤药综合征可能成为治疗前列腺癌的一种替代策略。
