Role of ncRNA-mediated Relocation of AR Transcription Units in Prostate Cancer

描述(申请人提供)：前列腺癌是男性最常见的非皮肤恶性肿瘤，死亡人数超过除肺癌以外的任何其他癌症。根据美国癌症协会(ACS)的数据，2007年美国约有218,890例新诊断的前列腺癌病例，约六分之一的男性将在其有生之年被诊断出患有前列腺癌。雄激素在促进前列腺癌的发生和发展中起着重要的作用。因此，了解处于前列腺癌研究中心阶段的雄激素受体(AR)靶基因表达的机制是非常必要的。尽管我们对AR调节基因转录的分子机制及其与前列腺癌的可能联系的了解正在增加，但有几个 有趣的问题仍有待回答。因此，该建议中的主要假设是，基于特定组蛋白标记“读取器”的共价修饰的基因调节区的ncRNA依赖的重新定位，如PC2，是包括AR在内的核受体转录作用的调控机制的关键组成部分。具体地说，这项研究旨在：1)将PC2的非组蛋白甲基化/去甲基化定义为负责全基因组AR转录程序的一种新的分子策略；2)确定雄激素诱导的AR靶基因在PcG小体和染色质间颗粒之间的重新定位以及ncRNAs的潜在参与；3)研究ncRNAs在调节雄激素依赖的基因调控程序中的作用及其与前列腺癌发生的潜在相关性。这项研究的主要新颖之处在于，它揭示了雄激素依赖基因调控程序所需的调控机制的一个新组成部分，它提供了一种生物学和临床上的创新机制，通过该机制，AR靶向基因部分地通过依赖于配体的动态定位从转录抑制型核体重新定位到允许核体，涉及非组蛋白PC2甲基化事件和由此产生的特异性ncRNA关联之间的功能相互作用。一般来说，这一机制可能有助于整合转录因子/共调节因子、非组蛋白蛋白甲基化和位于不同亚核结构中的ncRNAs的作用，实现核受体靶基因的协同激活。这项拟议研究的结果可能有助于开发新的前列腺诊断和治疗策略。 公共卫生相关性：前列腺癌是男性最常见的非皮肤恶性肿瘤，除肺癌外，导致的死亡人数比其他任何癌症都多。根据美国癌症协会(ACS)的数据，2007年美国约有218,890例新诊断的前列腺癌病例，约六分之一的男性将在其有生之年被诊断出患有前列腺癌。这项研究旨在提供一种生物学和临床上的创新机制，其中雄激素受体靶向基因的调控部分是通过配体依赖的动态重新定位，从转录抑制型到允许核体，涉及非组蛋白PC2甲基化事件和由此产生的特定非编码RNA关联之间的功能相互作用，从而促进新的前列腺癌诊断和治疗策略的发展。

DESCRIPTION (provided by applicant): Prostate cancer is the most common non-skin malignancy in men and is responsible for more deaths than any other cancer, except for lung cancer. According to the American Cancer Society (ACS), about 218,890 new cases of prostate cancer were diagnosed in the United States during 2007 and about 1 man in 6 will be diagnosed with prostate cancer during his lifetime. It is well established that androgen plays an important role in promoting prostate cancer initiation/development. Therefore, it is essential to understand the mechanism of androgen receptor (AR) target gene expression, which is at the center stage of prostate cancer research. Although our knowledge of the molecular mechanisms by which the AR regulates gene transcription and its possible link to prostate cancer is increasing, several interesting questions remain to be answered. Thus, the major hypothesis in this proposal is that ncRNA-dependent relocation of gene regulatory regions based on covalent modifications of specific histone mark "readers," such as Pc2, are critical components of the regulatory machinery underlying the transcriptional actions of nuclear receptors, including AR. Specifically, the proposed study aims to: 1) define non-histone methylation/demethylation of Pc2 as a novel molecular strategy responsible for genome-wide AR transcriptional programs; 2) determine the androgen-induced relocation of AR target genes between PcG bodies and interchromatin granules and the potential involvement of ncRNAs; 3) investigate the role of ncRNAs in modulating androgen-dependent gene regulatory programs and their potential relevance for the prostate cancer development. The major novel aspect of this study is that it uncovers a new component of the regulatory machinery required for androgen-dependent gene regulatory programs by providing a biologically and clinically innovative mechanism by which AR-targeted genes are regulated, in part, by the dynamic ligand-dependent relocation from transcriptional repressive to permissive nuclear bodies involving the functional interplay between the non-histone Pc2 methylation events and the resultant specific ncRNA associations. Generally, this mechanism may serve to integrate actions of transcription factor/co-regulators, non-histone protein methylation, and ncRNAs resident in distinct subnuclear architectural structures to achieve coordinated activation for nuclear receptor target genes. The results from the proposed study may facilitate the development of novel prostate diagnosis and therapeutic strategies. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common non-skin malignancy in men and is responsible for more deaths than any other cancer, except for lung cancer. According to the American Cancer Society (ACS), about 218,890 new cases of prostate cancer were diagnosed in the United States during 2007 and about 1 man in 6 will be diagnosed with prostate cancer during his lifetime. The proposed study aims to provide a biologically and clinically innovative mechanism by which androgen receptor-targeted genes are regulated, in part, by the dynamic ligand-dependent relocation from transcriptional repressive to permissive nuclear bodies involving the functional interplay between the non-histone Pc2 methylation events and the resultant specific non-coding RNA associations, thus facilitating the development of novel prostate diagnosis and therapeutic strategies.