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

基本信息

批准号：
8041089
负责人：
Hsing-Jien Kung
金额：
$ 30.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/8041089
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 Epidermal Growth Factor Receptor 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

项目摘要

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（由申请人提供）：雄激素受体在前列腺致癌作用及其过表达和异常激活中起着重要作用，被认为是发展耐Castration耐药性肿瘤的根本原因，目前，这违反了任何有效的治疗方法。作为转录因子，雄激素受体参与转录复合物的组装，包括目标基因组位点上的共激活剂。一类特殊的共激活因子是组蛋白修饰酶，最好的理解是组蛋白乙酰酶。新兴类别是组蛋白脱甲基酶，它可以重塑雄激素受体结合位点周围的染色质。因此，它们既是转录共激活因子和表观遗传调节剂。本提案基于我们对新型组蛋白脱甲基酶的鉴定，并具有强大的雄激素受体共激活剂的所有标志，并且在前列腺癌中过表达。它增强了雄激素反应，加速了细胞周期的进程，并表现出与已知的组蛋白脱甲基酶不同的底物特异性。有趣的是，它受生长因子的调节，并由酪氨酸激酶磷酸化。酶是细胞周期调节的，但也调节细胞周期。基于这些初步观察，我们希望阐明其生化特性作为脱甲基化酶，其作为信号传感器的调节及其作为雄激素受体共激活剂的生物学作用。还将评估它作为生物标志物和/或治疗靶标的潜力。公共卫生相关性：越来越多的证据表明，超过90％的耐castration前列腺癌已经进化出了由于雄激素受体突变而异常激活雄激素受体的方法，可以放大，内部雄激素的增加，内部雄激素的增加，后移植后的雄激素受体或雄激素受体或雄激素受体的相关性。因此，靶向异常激活的雄激素受体或其失调的共激活因子可能是干扰激素难治性肿瘤发展的最富有成果的策略。干扰配体结合的策略是一种选择，但不能靶向截断的雄激素受体。靶向共激活因子是另一种策略，但是大多数共激活因子不是酶，这使得小分子抑制剂的发展更加困难。我们发现，一种酶脱甲基酶是一种共激活剂，因此为这种干预提供了理想的目标。如果SAHA是组蛋白脱乙酰基酶和临床认可的药物的抑制剂，则是一个相关的例子，则这种新的组蛋白脱甲基酶可能是基于酶的前列腺癌靶标。它们在我们的初步数据中显示的前列腺癌标本中的一致过表达表明，它也可能是异常激活雄激素受体的良好生物标志物。该提案与前列腺癌的总体相关性包括：1）它提供了一种新的手柄，以了解雄激素受体活性的表观遗传调节，从而了解前列腺癌的发展。 2）它为前列腺癌发生中雄激素受体的转化和/或异常激活提供了潜在的新生物标志物，3）它提供了一个潜在的基于新酶的靶标，用于干扰前列腺癌发生。