mRNA Polyadenylation in Prostate Cancer

前列腺癌中的 mRNA 多聚腺苷酸化

• 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
• 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

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.

项目总结/摘要 前列腺癌是最常见的男性癌症，也是男性癌症的第二大病因 死亡前列腺癌细胞的一个关键生物学特性是它们的生长依赖于转录 雄激素受体（AR）。AR是由雄激素激活的，雄激素是雄性激素。 因此，晚期前列腺癌患者的有效治疗是雄激素剥夺疗法， 它阻断雄激素的作用，抑制AR，并阻止前列腺癌细胞的生长。的 雄激素剥夺疗法的局限性在于前列腺癌细胞最终通过 这些机制可以使AR重新激活。这个致命阶段被称为去势抵抗 前列腺癌（CRPC）。在这个建议中，我们已经确定了异常的mRNA多聚腺苷酸化作为一种调节， 促进CRPC中AR再激活的机制。前体RNA的剪接是一个生物学过程， 核心剪接体和剪接因子。选择性mRNA剪接是蛋白质组学的基础机制， 多样化，使几十万种不同的蛋白质产品能够从蛋白质中合成。 人类基因组中大约有20,000个基因。mRNA剪接对正常发育至关重要 和组织稳态，并且已知在包括癌症在内的病理学中会发生改变。一个关键的决策点， mRNA剪接是最后一个外显子的识别，其必须在3'末端被切割，然后才能添加相应的外显子。 poly（A）尾。这一过程称为切割和多聚腺苷酸化，由共有序列的结合指导。 AAUAAA多聚（A）位点在最后一个外显子上被一种多肽复合物所切割并聚腺苷酸化 特异性因子（CPSF）。我们的初步数据表明，表达的核心组成部分的CPSF 在前列腺癌中复合物显示改变的表达，这与侵袭性疾病特征相关 包括转移。我们发现了一种新的前列腺癌调节机制， 复合物，介导AR基因内含子3中替代AAUAAA poly（A）位点的利用， 协调驱动多种组成型活性AR变体蛋白表达的上游剪接事件 在CRPC细胞中。本研究的假设是，通过去调节CPSF， 作用促进多种AR变体的表达，这些变体共同促进CRPC和对AR的抗性。 靶向治疗。为了验证这一假设，我们将1）研究CPSF复合物的表达和活性 临床前列腺癌中的成分; 2）阐明CPSF复合物结合AR的机制 前体RNA并调节组成型活性AR变体的表达，以及3）测试核酸-前体RNA的功效。 基于我们已经开发的阻断CPSF与AR基因位点相互作用并抑制 AR变体蛋白的表达。总的来说，这项工作有望推进和联系mRNA的广泛领域 CRPC是通过多聚腺苷酸化和AR信号传导来治疗的，并且提供了预防或延迟CRPC的治疗机会。

项目成果

Androgen Receptor Dependence.

• DOI: 10.1007/978-3-030-32656-2_15
• 发表时间: 2019
• 期刊: Advances in experimental medicine and biology
• 作者: Chaturvedi AP;Dehm SM
• 通讯作者: Dehm SM

Androgen receptor variants: RNA-based mechanisms and therapeutic targets.

• DOI: 10.1093/hmg/ddaa089
• 发表时间: 2020-05
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Kiel T Tietz;S. Dehm

A pan-cancer transcriptome analysis of exitron splicing identifies novel cancer driver genes and neoepitopes.

• DOI: 10.1016/j.molcel.2021.03.028
• 发表时间: 2021-05-20
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Wang TY;Liu Q;Ren Y;Alam SK;Wang L;Zhu Z;Hoeppner LH;Dehm SM;Cao Q;Yang R
• 通讯作者: Yang R