Androgen Signaling and Coactivator Regulation in PCA

PCA 中的雄激素信号转导和共激活因子调节

• 批准号: 8145507
• 负责人: Hsing-Jien Kung
• 金额: $ 6.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145507
• 关键词: Androgen Receptor; Androgens; Antibodies; Arginine; Attention; Basic Science; Binding Sites; Biochemical; Biological; Biological Markers; Cancer Biology; Castration; Cell Cycle; Cell Cycle Progression; Cell Line; Complex; Coupled; Cyclin A; Data; Development; Disease; Enzymes; Epigenetic Process; Excision; Exhibits; Family; Gene Targeting; Genes; Genome; Growth; Growth Factor; Health; Histone Code; Histone Deacetylase Inhibitor; Histones; Hormones; In Vitro; Intervention; Knowledge; Ligand Binding; Lysine; Malignant neoplasm of prostate; Methylation; Molecular; Monitor; Mutation; Peptides; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Property; Protein Tyrosine Kinase; PubMed; Publications; Published Comment; Refractory; Regulation; Resistance; Role; Signal Transduction; Site; Specificity; Specimen; Substrate Specificity; Tail; Tissues; Transcription Coactivator; Transducers; Transfection; Translational Research; Vorinostat; Work; Xenograft procedure; base; cancer cell; chromatin immunoprecipitation; chromatin remodeling; clinically significant; effective therapy; enzyme substrate; fascinate; histone acetyltransferase; in vivo; inhibitor/antagonist; overexpression; progression marker; promoter; prostate carcinogenesis; public health relevance; receptor; receptor binding; receptor expression; response; small molecule; src-Family Kinases; therapeutic target; tumor

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.

描述(申请人提供)：雄激素受体在前列腺癌的发生中起重要作用，其过度表达和异常激活被认为是抗去势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，参与靶基因组上包括辅活化子在内的转录复合体的组装。一类特殊的辅活化子是组蛋白修饰酶，而最被理解的是组蛋白乙酰化酶。一个新出现的类别是组蛋白去甲基酶，它用于重塑雄激素受体结合部位周围的染色质。因此，它们既是转录共激活因子，又是表观遗传调节因子。目前的建议是基于我们鉴定的一种新的组蛋白去甲基酶，该酶具有雄激素受体的强辅助激活因子的所有特征，并且在前列腺癌中过度表达。它增强雄激素反应，加速细胞周期进程，并表现出不同于已知的组蛋白去甲基酶的底物特异性。有趣的是，它受生长因子调节，并被酪氨酸激酶磷酸化。该酶不仅调节细胞周期，还调节细胞周期。在这些初步观察的基础上，我们希望阐明其作为去甲基化酶的生化性质，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学作用。还将评估其作为生物标记物和/或治疗靶点的潜力。 公共卫生相关性：越来越多的证据表明，超过90%的去势耐受前列腺癌已经进化出异常激活雄激素受体的方式，这要么是由于雄激素受体突变、扩增、内分泌雄激素增加、雄激素受体翻译后修饰，要么是由于雄激素协同激活剂的结合。因此，靶向异常激活的雄激素受体或其失调的辅活化子可能是干预激素难治性肿瘤发展的最有效的策略。干扰配体结合的策略是一种选择，但它无法针对被截断的雄激素受体。靶向共激活剂是另一种策略，但大多数共激活剂不是酶，这使得小分子抑制剂的开发变得更加困难。我们发现组蛋白去甲基酶是一种共激活剂，因此为这种干预提供了一个理想的靶点。如果组蛋白脱乙酰酶抑制剂和临床批准的药物SAHA是一个恰当的例子，这种新的组蛋白去甲基酶可能是前列腺癌的理想酶靶点。我们的初步数据显示，它们在前列腺癌标本中持续过表达，这表明它也可能成为雄激素受体异常激活的良好生物标志物。这一建议与前列腺癌的总体相关性包括：1)它为理解雄激素受体活性的表观遗传调控从而前列腺癌的发生提供了一个新的句柄。2)它为前列腺癌中雄激素受体的转化和/或异常激活提供了一个潜在的新的生物标志物；3)它为干预前列腺癌的发生提供了一个潜在的基于酶的新靶点。