Androgen Signaling and Coactivator Regulation in PCA

雄激素受体在前列腺癌的发生及其过度表达中起重要作用 异常激活被认为是去势的潜在原因- 耐药肿瘤，目前没有任何有效的治疗方法。作为一种转录因子，雄激素 受体参与转录复合体的组装，包括靶分子上的辅活化子。 基因组站点。一类特殊的共激活剂是组蛋白修饰酶，也是最好的 所了解的是组蛋白乙酰基酶。一个新出现的类别是组蛋白去甲基酶，它的作用是 重塑雄激素受体结合部位周围的染色质。因此，他们都是 转录共激活因子和表观遗传调节因子。目前的建议是基于我们的身份识别 一种新的组蛋白去甲基酶，具有雄激素受体和 在前列腺癌中过度表达。它增强雄激素反应，加速细胞周期 进展，并表现出不同于已知组蛋白去甲基酶的底物专一性。 有趣的是，它受生长因子调节，并被酪氨酸激酶磷酸化。这种酶是 调节细胞周期，也调节细胞周期。基于这些初步观察，我们希望 阐明其作为脱甲基酶的生化性质，作为信号转导的调节， 以及作为雄激素受体辅助激活剂的生物效应。它作为生物标志物和/或 治疗的目标也将得到评估。

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.