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（由申请人提供）：雄激素及其受体 AR 是人类核受体 (NR) 超家族的成员，在导致全世界数千人死亡的前列腺癌 (PC) 和去势抵抗性前列腺癌 (CRPC) 中发挥着关键作用。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开发这种致命疾病未来疗法的关键。我们研究的长期目标是发现转录和表观基因组调控中 NR 功能的新成分，对人类疾病具有强大的转化意义。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 依赖性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性前列腺癌 (CRPC) 中发挥着先前未实现的关键作用。本期的目标 我们的工作是进行深入、综合的机制、全基因组、细胞和动物研究，以剖析这个新发现的信号模块在 CRPC 中 AR 功能中的作用。为了实现我们的研究目标，我们将利用跨学科知识和共同研究人员的互补专业知识，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。在具体目标中，我们将使用基于细胞和动物的模型，在体外和体内检查 WDR5 和 PKN1 在基因调控中的作用以及 CRPC 细胞功能的广泛分子细节。我们还将确定 CRPC 细胞中 WDR5 和 H3T11P 的基因特异性和全基因组定位谱。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且快速发展的概念，我们相信我们的工作处于当前激素信号传导知识的极限。因此，我们的研究结果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，从而显着推进该领域的发展。