CBP Bromodomain Antagonists Block Androgen Receptor in Prostate Cancer

CBP 溴结构域拮抗剂阻断前列腺癌中的雄激素受体

• 批准号: 7791094
• 负责人: SYED Shiraz MUJTABA
• 金额: $ 8.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791094
• 关键词: Acetylation; Address; Androgen Receptor; Apoptosis; Binding; Biochemical; Biological; Biological Assay; Bromodomain; CDKN1A gene; CREB-binding protein; Cancer Etiology; Cause of Death; Cell Cycle; Cell Cycle Arrest; Cell Proliferation; Cell Survival; Cells; Cellular Assay; Chemicals; Chromatin; Complex; DNA Binding; DNA Methyltransferase; DNA Modification Methylases; Data; Deacetylation; Development; Dose; EP300 gene; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epigenetic Process; Event; Fluorescence; Gene Targeting; Genes; Genotoxic Stress; Goals; Growth; HIV; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Individual; Inhibitory Concentration 50; Investigation; Kinetics; Knowledge; LNCaP; Ligands; Luciferases; Lysine; Malignant neoplasm of prostate; Mediating; Molecular; Mouse Mammary Tumor Virus; Organ Specificity; Outcome; Outcome Study; PC3 cell line; PTEN gene; Play; Post-Translational Protein Processing; Prostate; Prostate-Specific Antigen; Proteins; Publishing; Quantitative Reverse Transcriptase PCR; Receptor Activation; Recruitment Activity; Regulation; Reporter; Reporter Genes; Reporting; Research; Response Elements; Role; Site; Specificity; Structure; Structure-Activity Relationship; TP53 gene; Targeted Research; Testing; Therapeutic; Toxic effect; Transcriptional Activation; Transcriptional Regulation; analog; base; cancer cell; design; human CREBBP protein; inhibitor/antagonist; knock-down; men; new therapeutic target; oncoprotein p21; outcome forecast; promoter; receptor expression; receptor function; response; small molecule; therapeutic target; transcription factor; tumor

DESCRIPTION (provided by applicant): Prostate cancer (PCa) remains a leading cause of death in men. Androgen Receptor (AR) plays a central role in normal prostate development as well as regulating cell proliferation, differentiation and apoptosis in PCa. Resultantly, AR remains a valuable therapeutic target due to this organ specificity. Although it is known that CBP/p300 (CREB binding protein) mediated lysine acetylation of AR (ARKac) plays a vital role in AR activation and control of downstream target genes in prostate cells, the molecular events that follow ARKac remains unclear. Our study elucidated the mechanistic details of molecular events that follow CBP mediated acetylation of p53 on lysine 382 (p53Kac382) upon genotoxic stress. We showed that CBP is recruited to p53K382ac moiety by its bromodomain (CBP BRD): a specific molecular interaction that is essential for p53-induced transcriptional activation of the cyclin dependent kinase inhibitor, p21, involved in G1 cell cycle arrest. Preliminary data show that a small molecule inhibitor (SMI) of CBP BRD inhibits AR expression and transcriptional activity by downregulating prostate specific antigen (PSA) in LNCaP and PC3 cells. Here, we hypothesize that CBP BRD play a key role in ARKac-mediated regulation of target genes and cell fate decisions; therefore, highly selective SMIs for CBP BRD could alter the fate of the cancer cells to apoptosis. Therefore, the long-term goal of this research plan is to block the AR function in PCa. While multiple acetylation sites in AR have been reported, the specific effects of individual or combined acetylation of these lysine residues on AR activity remains to be clarified. Further, despite AR being a sequence-specific DNA binding transcription factor, the role of PTMs on chromatin as well as AR in regulating downstream genes is unknown. A multifaceted approach is proposed to address mechanistic underpinnings of AR transcriptional activation as a consequence of acetylation. Two specific aims are proposed to achieve this goal: (1) validate CBP BRD as a new therapeutic target for PCa; (2) dissect cellular response concomitant with epigenetic changes on global chromatin and AR target gene PSA. The emerging results from the proposed studies are expected to enhance our understanding of the molecular basis of AR function. Given the central role of AR in PCa, these studies will have important implications for the prognosis and treatment of human tumors.

描述（由申请人提供）： 前列腺癌（PCA）仍然是男性死亡的主要原因。雄激素受体（AR）在正常前列腺发育以及PCA中调节细胞增殖，分化和凋亡中起着核心作用。结果，由于这种器官特异性，AR仍然是有价值的治疗靶标。尽管众所周知，CBP/P300（CREB结合蛋白）介导的AR（ARKAC）赖氨酸乙酰化（ARKAC）在前列腺细胞中的AR激活和下游靶基因的控制中起着至关重要的作用，但遵循ARKAC的分子事件仍不清楚。我们的研究阐明了伴随遗传毒性应激对赖氨酸382（p53KAC382）上CBP介导的p53介导的乙酰化的分子事件的机械细节。我们表明，CBP是通过其溴结构域（CBP BRD）募集到P53K382AC部分的：一种特定的分子相互作用，对于p53诱导的细胞周期蛋白依赖性激酶抑制剂P21的转录激活至关重要，涉及G1细胞周期的p21。初步数据表明，CBP BRD的小分子抑制剂（SMI）通过下调LNCAP和PC3细胞中的前列腺特异性抗原（PSA）来抑制AR表达和转录活性。在这里，我们假设CBP BRD在ARKAC介导的靶基因和细胞命运决策的调节中起关键作用。因此，CBP BRD的高度选择性SMI可以改变癌细胞的命运对凋亡。因此，该研究计划的长期目标是阻止PCA中的AR功能。虽然已经报道了AR中的多个乙酰化位点，但这些赖氨酸残基对AR活性的个体或乙酰化的特定作用仍有待阐明。此外，尽管AR是序列特异性DNA结合转录因子，但PTM在调节下游基因中的作用是未知的。提出了一种多方面的方法来解决由于乙酰化而导致AR转录激活的机械基础。提出了两个具体目标来实现此目标：（1）验证CBP BRD作为PCA的新治疗靶点； （2）剖析细胞反应与全局染色质和AR靶基因PSA的表观遗传变化有关。拟议研究的新兴结果有望增强我们对AR功能分子基础的理解。鉴于AR在PCA中的核心作用，这些研究将对人类肿瘤的预后和治疗具有重要意义。