mRNA Polyadenylation in Prostate Cancer

前列腺癌中的 mRNA 多聚腺苷酸化

基本信息

批准号：
10062626
负责人：
Scott M. Dehm
金额：
$ 38.58万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10062626
关键词：
AR gene Affinity Androgen Receptor Androgens Antibodies Attention Automobile Driving Binding Biological Biological Markers Biological Process Biological Response Modifier Therapy Castration Cell Line Cessation of life Cleavage And Polyadenylation Specificity Factor Cleaved cell Clinical Complement Complex Consensus Coupling Data Development Diagnosis Disease Disease Progression Event Exons FDA approved Generations Genes Growth Homeostasis Human Genome Immunoprecipitation Individual Introns Knowledge Ligand Binding Domain Link Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Messenger RNA Minority Modeling Neoplasm Metastasis Oligonucleotides Organoids Outcome Pathology Patients Pharmaceutical Preparations Phenotype Poly A Poly(A) Tail Polyadenylation Polyadenylation Pathway Portraits Process Property Protein C Protein Isoforms Proteins Proteomics RNA RNA Splicing Receptor Signaling Recurrence Regulation Regulator Genes Resistance Resistance development Role Site Small Interfering RNA Spliceosomes Testing Therapeutic Tissue Stains Tissues Transcript Treatment Efficacy Variant Work Xenograft Model Xenograft procedure abiraterone advanced prostate cancer androgen deprivation therapy androgen sensitive blind castration resistant prostate cancer crosslink effective therapy efficacy testing epigenome genomic locus hormone therapy improved knock-down male male sex hormones member new therapeutic target novel therapeutics nucleic acid-based therapeutics polypeptide prevent prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer progression protein complex proteogenomics single molecule real time sequencing small molecule targeted treatment therapeutic evaluation transcription factor transcriptome tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Prostate cancer is the most frequently diagnosed male cancer and second leading cause of male cancer deaths. A key biological property of prostate cancer cells is that their growth is dependent on a transcription factor called the androgen receptor (AR). The AR is activated by androgen, the male sex hormone. Accordingly, an effective treatment for patients with advanced prostate cancer is androgen deprivation therapy, which blocks the effects of androgens, inhibits the AR, and halts the growth of prostate cancer cells. The limitation of androgen deprivation therapy is that prostate cancer cells eventually develop resistance through mechanisms that allow AR to become reactivated. This lethal stage is referred to as castration-resistant prostate cancer (CRPC). In this proposal, we have identified aberrant mRNA polyadenylation as a regulatory mechanism that promotes AR re-activation in CRPC. Splicing of pre-RNA is a biological process regulated by the core spliceosome and splicing factors. Alternative mRNA splicing is a mechanism underlying proteomic diversification, enabling several hundreds of thousands of different protein products to be synthesized from the approximately 20,000 genes encoded in the human genome. mRNA splicing is critical for normal development and tissue homeostasis, and is known to be altered in pathologies including cancer. One key decision point in mRNA splicing is recognition of the last exon, which must be cleaved at the 3’ end before addition of the poly(A) tail. This process, termed cleavage and polyadenylation, is directed by binding of the consensus AAUAAA poly(A) site in the last exon by a polypeptide complex called the cleavage and polyadenylation specificity factor (CPSF). Our preliminary data demonstrates that expression of core components of the CPSF complex display altered expression in prostate cancer, which is associated with aggressive disease features including metastasis. We have uncovered a new prostate cancer regulatory mechanism whereby the CPSF complex, mediates utilization of an alternative AAUAAA poly(A) site in intron 3 of the AR gene, which coordinates upstream splicing events that drive expression of multiple constitutively active AR variant proteins in CRPC cells. The hypothesis of this study is that aberrant AR mRNA polyadenylation via de-regulated CPSF action promotes expression of multiple AR variants that collectively promote CRPC and resistance to AR- targeted therapies. To test this hypothesis, we will 1) study the expression and activity of CPSF complex components in clinical prostate cancer; 2) elucidate the mechanisms by which the CPSF complex binds AR pre-RNA and regulates expression of constitutively active AR variants, and 3) test efficacy of nucleic acid- based therapeutics we have developed that block CPSF interaction with the AR gene locus and inhibit expression of AR variant proteins. Overall, this work is expected to advance and link the broad fields of mRNA polyadenylation and AR signaling, and provide therapeutic opportunities to prevent or delay CRPC.

项目摘要/摘要前列腺癌是最常见的男性癌症，是男性癌症的第二大原因死亡人数。前列腺癌细胞的关键生物学特性是它们的生长取决于转录因子称为雄激素受体（AR）。 AR被男性性激素雄激素激活。彼此之间，对晚期前列腺癌患者的有效治疗是雄激素剥夺疗法，阻断雄激素的作用，抑制AR，并停止前列腺癌细胞的生长。这雄激素剥夺疗法的限制是前列腺癌细胞有时会通过允许AR重新激活的机制。这个致命的阶段被称为cast割前列腺癌（CRPC）。在此提案中，我们已经确定异常的mRNA聚腺苷酸为调节促进CRPC中AR重新激活的机制。 pre-RNA的剪接是由核心剪接体和剪接因子。替代mRNA剪接是一种基础蛋白质组学的机制多样化，使数十万不同的蛋白质产物可以从大约20,000个基因在人类基因组中编码。 mRNA剪接对于正常发育至关重要和组织稳态，已知在包括癌症在内的病理中改变了。一个关键决策点 mRNA剪接是对最后一个外显子的识别，必须在添加之前在3'结束时切割。 poly（a）尾巴。该过程称为裂解和聚腺苷酸化，是通过共识的结合指导的最后一个外显子中的AAUAA poly（A）位点通过多肽复合物称为裂解和聚腺苷酸化特异性因子（CPSF）。我们的初步数据表明，CPSF的核心成分的表达复杂的显示改变了前列腺癌的表达，这与侵略性疾病特征有关包括转移。我们发现了一种新的前列腺癌调节机制，CPSF 复合物介导了AR基因内含子3中替代AAUAA poly（A）位点的利用坐标上游剪接事件，驱动多个组成型活性AR变体蛋白的表达在CRPC细胞中。这项研究的假设是，通过DEN调节的CPSF，异常的AR mRNA聚腺苷酸化作用促进了多种AR变体的表达，这些变体共同促进了CRPC和对AR的抗性靶向疗法。为了检验这一假设，我们将研究CPSF复合物的表达和活性临床前列腺癌的成分； 2）阐明CPSF复合物结合AR的机制预rna和调节组成性活性AR变体的表达，3）核酸的测试效率基于理论，我们开发了CPSF与AR基因基因座的相互作用并抑制 AR变体蛋白的表达。总体而言，这项工作预计将推进并链接mRNA的广泛领域聚腺苷酸化和AR信号传导，并提供预防或延迟CRPC的治疗机会。