Androgen Receptor-containing novel transcriptional complex for cancer-specific gene expression in therapy-resistant Prostate Cancer

含有雄激素受体的新型转录复合物，用于治疗耐药性前列腺癌中癌症特异性基因的表达

• 批准号: 9810306
• 负责人: Samikshan Dutta
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-04 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810306
• 关键词: Acetates; Address; Advanced Development; Affect; Androgen Receptor; Androgens; Antiandrogen Therapy; Binding; Cancer Patient; Cell Nucleus; Cell Surface Proteins; Cells; Cessation of life; ChIP-seq; Chromatin; Chromosomes; Clinical Trials; Complex; DNA; Development; Disease; Disease Progression; Gene Expression; Generations; Genes; Genetic Transcription; Hormones; Human; Knowledge; Length; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metastatic Prostate Cancer; Microscopy; Mutation; Neuropilin-2; Nuclear; Nuclear Envelope; Oncogenic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Prednisone; RNA Splicing; Receptor Signaling; Regulation; Research; Resistance; Resolution; Role; Testing; Tissues; Transcriptional Activation; Treatment Efficacy; Variant; abiraterone; androgen deprivation therapy; castration resistant prostate cancer; cellular targeting; chromosomal location; clinically significant; deprivation; docetaxel; effective therapy; efficacy testing; genome-wide analysis; high risk; human tissue; member; mortality; novel; novel therapeutic intervention; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer progression; resistance mechanism; scaffold; standard care; success; therapy resistant; transcription factor; transcriptome sequencing; tumor progression

Abstract Androgen Receptor containing novel transcriptional complex for cancer-specific gene expression in therapy-resistant Prostate Cancer. PI: Samikshan Dutta Several studies indicated the importance of AR-regulated gene expression in CRPC, prompting to the development of second-generation anti-androgen therapies such as enzalutamide and abiraterone acetate. These drugs show limited success for treating CRPC patients because of the emergence of several resistant mechanisms, which are either dependent or independent on AR. One such mechanism maintains AR axis in therapy resistant-CRPC by expressing the splice variants of AR that can function despite enzalutamide treatment. AR specific activating mutations are also observed following abiraterone or enzalutamide treatment. To circumvent these resistant mechanisms, a better approach would be to inhibit AR functions directly by targeting its associated components of gene transcription. Our current study has indicated a CRPC-specific transcriptional complex where AR is acting as a member. We observed that the nuclear localization of AR and its splice variant is dependent on Neuropilin-2 (NRP2) in advanced PCa. NRP2 is a glycosylated, non-kinase cell surface protein, whose expression is associated with PCa-specific death. With the help of immunoelectron and super-resolution microscopy we observed NRP2 is present in the nuclear membrane of CRPC cells. Further, mass spectrometry and CHIP-sequencing analysis revealed that NRP2 helps AR and/or its splice variants to bind to the specific chromosome location for gene transcription. We therefore hypothesized that NRP2 in the nucleus is critical for AR driven oncogenic transcription and thus promotes aggressive CRPC. To address the hypothesis, we will study how NRP2-AR interaction induces CRPC specific gene expression. In support of our hypothesis, we found that NRP2 is upregulated following androgen deprivation in PCa cells as well as during metastatic progression in human PCa tissues. We also observed that the expression of nuclear NRP2 increases with higher Gleason pattern. Thus, depleting nuclear NRP2 can be an effective strategy to inhibit the AR-mediated global transcriptional activation in combination with the standard therapy. Current proposal thus implies the potential for the development of novel therapeutic approach against metastatic and therapy-resistant PCa.

摘要 含雄激素受体的新型肿瘤特异性基因转录复合物 在治疗抵抗性前列腺癌中的表达。 PI：Samikshan Dutta 一些研究表明AR调节的基因表达在CRPC中的重要性，提示 第二代抗雄激素治疗如恩杂鲁胺和 醋酸阿比特龙这些药物在治疗CRPC患者方面显示出有限的成功， 出现了几种耐药机制，这些机制要么依赖于AR，要么不依赖于AR。 一种这样的机制是通过表达剪接来维持AR轴在治疗抗性CRPC中。 尽管Enzalutamide治疗，AR变体仍能发挥作用。AR特异性激活突变 也在阿比特龙或恩杂鲁胺治疗后观察到。为了规避这些阻力， 因此，更好的方法是通过靶向其相关的AR功能来直接抑制AR功能。 基因转录的组成部分。我们目前的研究表明，CRPC特异性转录 其中AR作为成员。我们观察到AR及其受体的核定位， 剪接变异体在晚期PCa中依赖于神经纤毛蛋白-2（NRP 2）。NRP 2是糖基化的， 非激酶细胞表面蛋白，其表达与PCa特异性死亡相关。与 借助免疫电镜和超分辨率显微镜，我们观察到NRP 2存在于 CRPC细胞的核膜。此外，质谱和CHIP测序分析 揭示NRP 2帮助AR和/或其剪接变体结合到特定的染色体位置， for gene基因transcription转录.因此，我们假设核中的NRP 2对于AR是至关重要的。 驱动致癌转录，从而促进侵袭性CRPC。解决 假设，我们将研究NRP 2-AR相互作用如何诱导CRPC特异性基因表达。在 支持我们的假设，我们发现NRP 2在雄激素剥夺后上调， PCa细胞以及在人PCa组织中的转移进展期间。我们还观察到 核NRP 2表达随Gleason分型增高而增加。因此， NRP 2可能是一种有效的抑制AR介导的转录激活的策略。 与标准疗法相结合。因此，目前的提议意味着， 开发针对转移性和治疗抗性PCa的新治疗方法。