Transcription repression in prostate cancer

描述（由申请人提供）：染色质修饰的改变在肿瘤发生、疾病进展和治疗抗性中起主要作用。在雄激素受体活性恢复的情况下，染色质景观也发生了改变，这种雄激素受体活性被认为是促进去势抵抗性前列腺癌（CPRC）的原因。我们在这里描述了一个研究不足的转录抑制复合物，包括两个蛋白质，非常规的前折叠蛋白RBP 5相互作用（URI）和雄激素受体捕获克隆27（ART-27），调节染色质影响AR和聚合酶结合。我们发现ART-27被排除在复发性前列腺癌的细胞核之外，并且对于AR拮抗剂作用至关重要。URI和ART-27在雄激素刺激之前稳定结合于染色质，并且URI的消耗导致H3 K9三甲基化减少以及Nkx3.1基因调控序列上AR和聚合酶募集增加。最近，我们已经表明URI与含KAP 1蛋白的复合物相互作用，以调节高拷贝数DNA重复序列，所述DNA重复序列占人类基因组的40%以上，并且是最近活跃的逆转录转座子的结果。LINE-1逆转录元件编码的核酸内切酶的表达与基因融合的形成有关，如TMPRSS 2/ERG，我们提出的证据表明，ART-27/URI复合物的错误调节导致前列腺癌中逆转录元件表达增加，基因融合增加和AR靶基因调节改变。关于ART-27和URI的核作用知之甚少，更不用说retroelement表达对癌症进展和/或融合基因产物产生的贡献了。因此，我们的目的是1）检查ART-27消融对前列腺细胞生长和前列腺癌小鼠模型的影响2）确定ART-27和URI介导的基因和逆转录因子抑制的机制3）确定前列腺癌细胞中逆转录因子表达的AR依赖性和ART-27/URI蛋白复合物在TMPRSS 2/ERG易位中的作用.

DESCRIPTION (provided by applicant): Alteration of chromatin modification plays a major role in tumorigenesis, disease progression and therapeutic resistance. The chromatin landscape is also altered in the case of resurgent androgen receptor activity that is thought to promote castration resistant prostate cancer (CPRC). We describe here an understudied transcription repression complex including two proteins, Unconventional prefoldin RBP5 interactor (URI) and Androgen Receptor Trapped clone 27 (ART-27) that modulate chromatin to impact AR and polymerase binding. We showed that ART-27 is excluded from the nucleus in recurrent prostate cancer and is critical for AR antagonist action. URI and ART-27 are stably bound to chromatin prior to androgen stimulation and depletion of URI results in diminished H3K9 tri-methylation and increased AR and polymerase recruitment on Nkx3.1 gene regulatory sequences. Recently, we have shown that URI interacts with a KAP1 protein- containing complex to regulate high copy number DNA repeats that comprise greater than 40% of the human genome and are a result of recently active retrotransposons. Expression of the endonuclease encoded by the LINE-1 retroelement is linked to formation of genes fusions, such as TMPRSS2/ERG and we present evidence that misregulation of the ART-27/URI complex results in increased retroelement expression, increased gene fusion and altered regulation of AR target genes in prostate cancer. Very little is known about the nuclear role of ART-27 and URI, much less the contribution of retroelement expression to cancer progression and/or generation of fusion gene products. Thus, our aims are to 1) Examine the impact of ART-27 ablation on prostate cell growth and in mouse models of prostate cancer 2) Determine the mechanism of ART-27 and URI- mediated gene and retroelement repression 3) Determine the AR dependence of retroelement expression in prostate cancer cells and the role of the ART-27/URI protein complex in TMPRSS2/ERG translocation.