雄激素受体剪切变异体在前列腺癌中介导雄激素调节基因转录重编程机制的研究

项目名称： 雄激素受体剪切变异体在前列腺癌中介导雄激素调节基因转录重编程机制的研究

项目编号： No.31501052

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 卢绩

作者单位： 吉林大学

项目金额： 20万元

中文摘要： 雄激素受体（AR）在前列腺癌进展中起重要作用。雄激素受体剪切变异体（AR-Vs）是全长AR截短的亚型，不需雄激素激活即具有转录活性，可能是雄激素剥夺治疗抵抗和去势抵抗性前列腺癌（CRPC）进展的重要机制之一。但关于AR-Vs对于前列腺癌雄激素调节基因转录的影响尚不清楚。在前期工作中，我们发现AR-Vs可能引起前列腺癌细胞中AR全基因组结合位点的重新分布，结合FOXA1和表观遗传学修饰在AR与DNA结合中所起的作用，我们提出假说认为AR-Vs能够介导雄激素调节基因转录的重编程。本项目拟采用ChIP-seq技术，鉴别AR-Vs敲低后全基因组结合位点的变化及其FOXA1结合情况和表观基因组学特征，结合RNA-seq所获得的差异性表达的雄激素调节基因，阐明AR-Vs介导雄激素调节基因转录重编程的机制。这不仅有助于理解AR-Vs在CRPC进展中的作用，而且有助于筛选CRPC新的肿瘤标志物及治疗靶点。

中文关键词： 前列腺癌；雄激素受体；剪切变异体；雄激素调节基因；全基因组结合位点

英文摘要： Androgen receptor (AR) plays important roles in prostate cancer progression. The spliced variant forms of AR (AR-Vs) are truncated isoforms and have constitutive activity without androgen. Therefore, AR-Vs may be one of the important mechanisms for androgen deprivation therapy resistance and castration-resistant prostate cancer (CRPC) progression. But it is not clear that if AR-Vs could affect the modulation of androgen-regulated genes. In previous work, we found that AR-Vs could cause re-distribution of the genome-wide AR DNA binding sites. Combining roles of FOXA1 and epigenetic modifications in AR DNA binding, we hypothesize that AR-Vs could mediate transcriptional reprogramming of androgen-regulated genes in prostate cancer. We plan to perform Chromatin immunoprecipitation followed by DNA–sequencing (ChIP-seq) analysis to identify changes of genome-wide AR binding sites after knocking down AR-Vs. Their FOXA1 binding and epigenomic features can also be identified. Intergrated analysis with differential expression of androgen-regulated genes through RNA-seq, we could clarify the mechanism how AR-Vs mediate transcriptional reprogramming of androgen-regulated genes. This not only helps us understand roles of AR-Vs in CRPC progression, but also screen new tumor markers and theraputic targets for CRPC.

英文关键词： prostate cancer;androgen receptor;splicing variants;androgen-regulated genes;cistrome