Mechanistic Roles of Long mcRNA-regulated Gene Transcription in Prostate Cancer

项目摘要 前列腺癌是男性最常见的非皮肤性恶性肿瘤，导致的死亡人数更多。 比任何其他癌症都要多，除了肺癌。根据美国癌症协会(ACS)的数据，大约 2007年，美国新诊断出218,890例前列腺癌病例，约每6人中就有1人被诊断出患有前列腺癌 将在他的有生之年被诊断出患有前列腺癌。众所周知，雄激素对人体健康的影响 在促进前列腺癌发生/发展中的重要作用。因此，有必要了解 前列腺癌中心期雄激素受体(AR)靶基因表达的机制 研究。尽管我们对AR调节基因转录的分子机制的了解 而且它与前列腺癌的可能联系正在增加，几个有趣的问题仍然有待回答。 因此，这个建议的主要假设是依赖于ncRNA的基因调节区的重新定位。 基于特定组蛋白标记的共价修饰，读取器，如PC2，是 核受体转录活动的调控机制，包括AR。具体地说， 拟议的研究旨在：1)将PC2的非组蛋白甲基化/去甲基化定义为一种新的分子策略 负责全基因组AR转录程序；2)确定雄激素诱导的AR重新定位 PcG小体和间染色质颗粒之间的靶基因及ncRNAs的潜在参与；3) 研究ncRNAs在调节雄激素依赖性基因调控程序中的作用及其机制 与前列腺癌发展的潜在相关性。这项研究的主要新奇之处在于它 发现雄激素依赖基因调控所需的调控机制的一个新组成部分 通过提供一种生物和临床创新机制，使AR靶向基因 部分受配体依赖的动态重新定位从转录抑制到允许的调节 核小体涉及非组蛋白PC2甲基化事件和 由此产生的特定的ncRNA关联。一般而言，该机制可用于整合 转录因子/共调节因子、非组蛋白甲基化和位于不同亚核的ncRNAs 构建结构，以实现核受体靶基因的协调激活。结果来自于 这项拟议的研究可能有助于开发新的前列腺癌诊断和治疗策略。

Project Summary 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.