Integrating Epigenomic and Nuclear Receptor Signaling in Castrate Resistant Prostate Cancer

整合表观基因组和核受体信号在去势抵抗性前列腺癌中的应用

• 批准号: 9103013
• 负责人: Sarki A. Abdulkadir
• 金额: $ 44.19万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103013
• 关键词: Androgen Antagonists; Androgens; Animal Model; Animals; Biochemistry; Biological Models; Biology; Breast Cancer Cell; Cancer Etiology; Cell Cycle; Cell Proliferation; Cell model; Cell physiology; Cells; Cessation of life; Complex; Development; Disease; Drug Targeting; Epigenetic Process; Event; Future; Gene Activation; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genome; Glucocorticoid Receptor; Goals; Histone H3; Histones; Hormone Receptor; Hormones; Human; Human Characteristics; In Vitro; Knowledge; Lead; Lysine; MLL gene; Malignant Neoplasms; Malignant neoplasm of prostate; Methyltransferase; Mitosis; Modeling; Modification; Molecular; Molecular Biology; Nuclear Hormone Receptors; Nuclear Receptors; Nucleosomes; Outcome; Pathway interactions; Patients; Phase; Phosphorylation; Phosphotransferases; Physiology; Play; Protein Kinase; Proteins; RNA Interference; Receptor Signaling; Recruitment Activity; Refractory; Regulation; Research; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Therapeutic; Thinking; Threonine; Tumorigenicity; Vitamins; Work; androgenic; base; cohort; epigenome; epigenomics; genetic signature; genome-wide; histone modification; human disease; in vivo; killings; member; men; neoplastic cell; new therapeutic target; novel; novel therapeutics; prostate cancer cell; public health relevance; receptor; receptor function; research study; steroid hormone; therapy resistant; transcription factor

 DESCRIPTION (provided by applicant): Androgen and its receptor AR, which is a member of the human nuclear receptor (NRs) superfamily, play critical roles in prostate cancer (PC) and castrate resistant prostate cancer (CRPC) that kills thousands of people world-wide. We posit that a better understanding of NR signaling pathway and its integration in epigenomic signaling are keys for development of future therapeutics of this deadly disease. The long term goal of our research is to discover novel components of NR function in transcriptional and epigenomic regulation with strong translational implications in human diseases. The protein kinase termed PKN1 plays a critical role in AR dependent gene regulation by establishing an epigenomic marking (histone H3 threonine 11 phosphorylation (H3T11P)) on nucleosomes at AR target genes. We hypothesize that the PKN1-H3T11P- WDR5 signaling module plays a previously unrealized and critical role in castrate resistant prostate cancer (CRPC). The goal of this present work is to perform in depth and integrative mechanistic, genome-wide, cellular and animal based studies to dissect the role of this newly discovered signaling module in AR function in CRPC. To achieve our research goals, we will utilize interdisciplinary knowledge and complementary expertise of the co-investigators spanning biochemistry, patho-physiology, genome biology, animal and cellular models of PC and molecular biology. In Specific Aims, we will examine in extensive molecular details the role of WDR5, and PKN1 in gene regulation, and CRPC-cell function in vitro and in vivo using cell and animal based models. We will also determine the gene-specific and genome-wide localization profiles of WDR5 and H3T11P in CRPC cells. Epigenomic markings and identification of their effector proteins in hormone action are new and rapidly evolving concepts and we believe our work lies at the limit of current knowledge of hormone signaling. Our findings will thus significantly advance the field by providing a better understanding of the role of epigenomic modifications and their effector proteins in nuclear receptor action and in human diseases including CRPC.

 描述(申请人提供)：雄激素及其受体AR是人类核受体(NRS)超家族的成员，在前列腺癌(PC)和去势抵抗型前列腺癌(CRPC)中发挥关键作用，后者在全球范围内导致数千人死亡。我们认为，更好地了解NR信号通路及其在表观基因组信号中的整合是发展这种致命疾病未来治疗的关键。我们研究的长期目标是发现NR在转录和表观基因组调控中的新成分，在人类疾病中具有很强的翻译意义。被称为PKN1的蛋白激酶通过在AR靶基因的核小体上建立表观基因组标记(组蛋白H3苏氨酸11磷酸化(H3T11P))，在AR依赖的基因调控中发挥关键作用。我们假设PKN1-H3T11P-WDR5信号模块在去势抵抗型前列腺癌(CRPC)中发挥了以前没有意识到的关键作用。这份礼物的目的是 工作是进行深入和综合的机制，全基因组，细胞和动物为基础的研究，以剖析这个新发现的信号模块在CRPC的AR功能中的作用。为了实现我们的研究目标，我们将利用合作研究人员的跨学科知识和互补专业知识，涵盖生物化学、病理生理学、基因组生物学、PC的动物和细胞模型以及分子生物学。在特定的目标中，我们将利用细胞和动物模型，广泛地从分子细节上研究WDR5和PKN1在基因调控中的作用，以及CRPC细胞在体外和体内的功能。我们还将确定WDR5和H3T11P在CRPC细胞中的基因特异性和全基因组定位。表观基因组标记及其在激素作用中的效应蛋白的鉴定是新的和快速发展的概念，我们相信我们的工作存在于目前对激素信号转导的知识的限制。因此，我们的发现将通过更好地理解表观基因组修饰及其效应蛋白在核受体作用和包括CRPC在内的人类疾病中的作用，从而显着推动该领域的发展。