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

描述（由申请人提供）：前列腺癌是男性中最常见的非皮肤恶性肿瘤，其死亡率高于除肺癌外的任何其他癌症。根据美国癌症协会（ACS）的数据，2007年美国诊断出约218，890例前列腺癌新病例，约六分之一的男性将在其一生中被诊断出患有前列腺癌。众所周知，雄激素在促进前列腺癌的发生/发展中起着重要作用。因此，了解雄激素受体（AR）靶基因的表达机制是前列腺癌研究的核心。虽然我们对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，但一些研究表明， 有趣的问题仍有待回答。因此，该提案中的主要假设是，基于特定组蛋白标记“阅读器”（如Pc 2）的共价修饰的基因调控区的ncRNA依赖性重新定位是核受体（包括AR）转录作用的调控机制的关键组成部分。具体而言，拟议的研究旨在：1）将Pc 2的非组蛋白甲基化/去甲基化定义为负责全基因组AR转录程序的新分子策略; 2）确定雄激素诱导的AR靶基因在PcG体和染色质间颗粒之间的重新定位以及ncRNA的潜在参与; 3）研究ncRNA在调节雄激素依赖性基因调控程序中的作用及其与前列腺癌发展的潜在相关性。这项研究的主要新颖之处在于，它揭示了雄激素依赖性基因调控程序所需的调控机制的一个新组成部分，通过提供一种生物学和临床创新机制，部分调控AR靶向基因，通过从转录抑制到允许的核小体的动态配体依赖性重新定位，涉及非-组蛋白Pc 2甲基化事件和由此产生的特异性ncRNA关联。通常，这种机制可以用于整合转录因子/辅助调节因子、非组蛋白甲基化和存在于不同亚核结构结构中的ncRNA的作用，以实现核受体靶基因的协调激活。这项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：前列腺癌是男性中最常见的非皮肤恶性肿瘤，其死亡率高于除肺癌外的任何其他癌症。根据美国癌症协会（ACS）的数据，2007年美国诊断出约218，890例前列腺癌新病例，约六分之一的男性将在其一生中被诊断出患有前列腺癌。这项拟议的研究旨在提供一种生物学和临床创新机制，通过这种机制，雄激素受体靶向基因受到调节，部分是通过从转录抑制性核小体到允许性核小体的动态配体依赖性重新定位，涉及非组蛋白Pc 2甲基化事件和由此产生的特异性非编码RNA关联之间的功能相互作用，从而促进新的前列腺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.