Integrating Epigenomic and Nuclear Receptor Signaling in Castrate Resistant Prostate Cancer

 描述（由申请人提供）：雄激素及其受体AR是人核受体（NR）超家族的成员，在前列腺癌（PC）和去势抵抗性前列腺癌（CRPC）中发挥关键作用，在全球范围内导致数千人死亡。我们认为，更好地了解NR信号通路及其整合在表观基因组信号是未来开发这种致命疾病的治疗方法的关键。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功能的新组分，其在人类疾病中具有强烈的翻译意义。蛋白激酶PKN 1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（H3 T11 P）），在AR依赖性基因调控中发挥关键作用。我们假设PKN 1-H3 T11 P-WDR 5信号传导模块在去势抵抗性前列腺癌（CRPC）中起着以前未认识到的关键作用。这个礼物的目的 我们的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传导模块在CRPC中AR功能的作用。为了实现我们的研究目标，我们将利用跨学科的知识和合作研究人员的互补专业知识，包括生物化学，病理生理学，基因组生物学，PC和分子生物学的动物和细胞模型。在具体目标中，我们将使用细胞和动物模型在体外和体内研究WDR 5和PKN 1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WDR 5和H3 T11 P的基因特异性和全基因组定位谱。表观基因组标记及其效应蛋白在激素作用中的识别是新的和快速发展的概念，我们相信我们的工作是在激素信号传导的现有知识的极限。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来显着推进该领域。

 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.