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

项目摘要 前列腺癌是男性中最常见的非皮肤恶性肿瘤， 比其他任何癌症都多，除了肺癌。根据美国癌症协会（ACS）的数据， 2007年，美国诊断出218，890例新的前列腺癌病例，约1/6的男性 会被诊断出患有前列腺癌众所周知，雄激素在 在促进前列腺癌发生/发展中的重要作用。因此，了解 雄激素受体（AR）靶基因表达的机制，这是前列腺癌的中心阶段 research.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也在增加，但仍有几个有趣的问题有待回答。 因此，该提议中的主要假设是基因调控区的ncRNA依赖性重新定位， 基于共价修饰的特定组蛋白标记“阅读器”，如Pc 2，是免疫系统的关键组成部分。 调节机制的核受体，包括AR的转录作用的基础。具体而言是 拟开展的研究旨在：1）将Pc 2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）决定雄激素诱导的AR重新定位 PcG小体和染色质间颗粒之间的靶基因以及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， 与前列腺癌发展的潜在相关性。本研究的主要创新之处在于， 揭示了雄激素依赖性基因调控所需的调控机制的一个新组成部分， 通过提供生物学和临床创新机制， 调节，部分，由动态配体依赖性搬迁从转录抑制到允许 涉及非组蛋白Pc 2甲基化事件和非组蛋白Pc 2甲基化事件之间的功能相互作用的核小体， 产生特异性ncRNA关联。一般来说，这一机制可用于整合以下方面的行动： 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中的ncRNA 构建结构以实现核受体靶基因的协调激活。的结果 这项研究可能有助于开发新的前列腺诊断和治疗策略。

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.