Androgen Signaling and Coactivator Regulation in PCA

描述（申请人提供）：雄激素受体在前列腺癌发生过程中起着重要作用，其过表达和异常激活被认为是去势抵抗肿瘤发生的根本原因，目前尚无有效的治疗方法。雄激素受体作为一种转录因子，参与包括辅激活因子在内的转录复合体在靶基因组位点的组装。一类特殊的共激活因子是组蛋白修饰酶，其中了解最多的是组蛋白乙酰化酶。新近出现的一类是组蛋白去甲基化酶，其作用是重塑雄激素受体结合位点周围的染色质。因此，它们既是转录辅激活因子又是表观遗传调控因子。目前的建议是基于我们鉴定了一种新的组蛋白去甲基化酶，它具有雄激素受体强辅激活因子的所有特征，并且在前列腺癌中过表达。它增强雄激素反应，加速细胞周期进程，并表现出不同于已知组蛋白去甲基化酶的底物特异性。有趣的是，它受生长因子调控，并被酪氨酸激酶磷酸化。该酶受细胞周期调节，但也调节细胞周期。基于这些初步观察，我们希望阐明其作为去甲基化酶的生化特性，作为信号换能器的调节作用，以及作为雄激素受体辅激活剂的生物学效应。它作为生物标志物和/或治疗靶点的潜力也将被评估。

DESCRIPTION (provided by applicant): Androgen receptor plays a significant role in prostate carcinogenesis and its overexpression and aberrant activation are considered to be the underlying cause for the development of castration-resistant tumors, which at present defy any effective treatment. As a transcriptional factor, androgen receptor is involved in the assembly of transcriptional complex including coactivators on the target genome site. One special class of coactivators are histone modifying enzymes and the best understood are histone acetylases. A newly emerging class is histone demethylase, which serves to remodel the chromatin surrounding the androgen receptor binding site. They are thus both transcriptional coactivator and epigenetic regulator. The present proposal is based on our identification of a new histone demethylase with all the hallmarks of a strong coactivator of androgen receptor and is overexpressed in prostate cancer. It enhances androgen response, accelerates cell cycle progression, and exhibits a substrate specificity different from the known histone demethylases. Intriguingly, it is regulated by growth factor and is phosphorylated by tyrosine kinases. The enzyme is cell cycle regulated but also regulates cell cycle. Based on these preliminary observations, we wish to elucidate its biochemical properties as a demetylation enzyme, its regulation as a signal transducer, and its biological effects as an androgen receptor coactivator. Its potential as a biomarker and/or a target for therapy will also be evaluated. PUBLIC HEALTH RELEVANCE: Increasing evidence suggests that over 90% of castration-resistant prostate cancers have evolved ways to aberrantly activate androgen receptor either due to androgen receptor mutations, amplification, increase of intracrine androgen, posttranslational modification of androgen receptor or association of deregulated coactivators. Thus, targeting aberrantly activated androgen receptor or its dysregulated coactivators is likely to be the most fruitful strategy to interfere with the development of hormone-refractory tumors. Strategy to interfere with ligand binding is one option, but it fails to target truncated androgen receptor. Targeting co-activators is another strategy, but most of the co-activators are not enzymes, which makes the development of small-molecule inhibitors more difficult. Our finding that histone demethylase, an enzyme, is a coactivator thus offers an ideal target for this intervention. If SAHA, an inhibitor for histone deacetylase and a clinically approved drug, is a pertinent example, this new histone demethylase could be an ideal enzyme-based target for prostate cancer. Their consistent overexpression in prostate cancer specimens shown in our preliminary data suggests it could also potentially be a good biomarker for aberrant activation of androgen receptor. The overall relevance of this proposal to prostate cancer includes : 1) It offers a new handle to understand the epigenetic regulation of androgen receptor activity and thus prostate cancer development. 2) It offers a potentially new biomarker for transformation and/or aberrant activation of androgen receptor in the prostate carcinogenesis, and 3) It offers a potentially new enzyme-based target for interfering with prostate carcinogenesis.