Transcription repression in prostate cancer

前列腺癌中的转录抑制

基本信息

批准号：
9449390
负责人：
Susan K. Logan
金额：
$ 40.26万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9449390
关键词：
Ablation Affect Androgen Receptor Androgens Automobile Driving Binding Biological Assay Cell Nucleus Chromatin Chromatin Structure Code Complex DNA Sequence Rearrangement DNA copy number Data Dependence Disease Disease Progression ERG gene Event Fostering Funding Gene Expression Gene Fusion Gene Targeting Generations Genes Genetic Transcription Genome Stability Genomic Instability Genomics Goals Grant HDAC1 gene Histone Deacetylase Human Genome Individual Life Link Malignant neoplasm of prostate Mediating Messenger RNA Methylation Modeling Modification Molecular Morphology Multiprotein Complexes Mus Nuclear PTEN gene Play Polymerase Prostate Prostatic Neoplasms Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins RNA Polymerase II Recurrence Regulation Regulator Genes Repression Resistance Retroelements Retrotransposition Retrotransposon Role SETDB1 gene Site Small Interfering RNA TMPRSS2 gene TP53 gene Testing Thinking Transcription Coactivator Transcription Repressor/Corepressor Transcriptional Regulation UXT gene Up-Regulation androgen sensitive castration resistant prostate cancer cell growth chromatin modification endonuclease fusion gene gene product gene repression gene translocation heterochromatin-specific nonhistone chromosomal protein HP-1 in vivo insight knock-down mouse model prefoldin promoter prostate cancer cell prostate cancer model prostate carcinogenesis protein complex public health relevance recruit therapy resistant transcription factor tumor progression tumor xenograft tumorigenesis

项目摘要

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.

描述（由申请人提供）：染色质修饰的改变在肿瘤发生、疾病进展和治疗抵抗中起着重要作用。在雄激素受体活性复苏的情况下，染色质景观也会发生改变，这种活性被认为会促进去势抵抗性前列腺癌（CPRC）。我们在这里描述了一种正在研究的转录抑制复合物，包括两种蛋白质，非常规前折叠蛋白 RBP5 相互作用蛋白 (URI) 和雄激素受体捕获克隆 27 (ART-27)，它们调节染色质以影响 AR 和聚合酶的结合。我们发现，在复发性前列腺癌中，ART-27 被排除在细胞核之外，并且对于 AR 拮抗剂的作用至关重要。在雄激素刺激之前，URI 和 ART-27 与染色质稳定结合，URI 的消耗会导致 H3K9 三甲基化减少，并增加 Nkx3.1 基因调控序列上的 AR 和聚合酶募集。最近，我们发现 URI 与包含 KAP1 蛋白的复合物相互作用，调节高拷贝数 DNA 重复，这些重复包含超过 40% 的人类基因组，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，例如TMPRSS2/ERG，我们提供的证据表明ART-27/URI复合物的错误调节会导致逆转录元件表达增加、基因融合增加和调节改变前列腺癌中 AR 靶基因的研究。关于 ART-27 和 URI 的核作用知之甚少，更不用说逆转录元件表达对癌症进展和/或融合基因产物产生的贡献了。因此，我们的目标是 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元件抑制的机制 3) 确定 AR 依赖性前列腺癌细胞中逆转录元件表达的影响以及 ART-27/URI 蛋白复合物在 TMPRSS2/ERG 易位中的作用。