The Role of YY1 in Castration-Resistant Prostate Cancer

YY1 在去势抵抗性前列腺癌中的作用

基本信息

批准号：
10451828
负责人：
Ling Cai
金额：
$ 42.93万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451828
关键词：
ATAC-seq Affect Androgen Antagonists Androgen Receptor Androgens BRD2 gene Binding Binding Sites Bromodomain Cancer Patient Cell Line Cell model Cells ChIP-seq Chromatin Clinic Clinical Complex DNA Binding Data Data Set Development Disease Disease Progression Enzymes Gene Activation Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genetically Engineered Mouse Genomics Glycolysis Glycolysis Pathway Goals Growth Hormones In Vitro Left Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Maps Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Metabolism Modeling Molecular Mus Oncogenic Outcome Pathway interactions Patients Pharmacology Phenotype Primary Neoplasm Prognosis Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins RNA Splicing Receptor Signaling Regulator Genes Research Resistance Role Sampling Side Signal Transduction Site TP53 gene Terminal Disease Testing Therapeutic Translating Treatment Failure Tumorigenicity VCaP Validation Variant Warburg Effect YY1 Transcription Factor Zinc Fingers advanced prostate cancer base castration resistant prostate cancer cell growth clinically relevant cofactor cohort enzyme pathway experimental study improved in vivo Model inhibitor innovation insight knock-down loss of function metabolomics mouse model novel novel strategies novel therapeutic intervention novel therapeutics overexpression programs prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer progression prostate carcinogenesis recruit standard care targeted agent therapy development therapy resistant transcription factor transcriptome sequencing treatment strategy tumor tumor metabolism

ATAC-seq Affect Androgen Antagonists Androgen Receptor Androgens BRD2 gene Binding Binding Sites Bromodomain Cancer Patient Cell Line Cell model Cells ChIP-seq Chromatin Clinic Clinical Complex DNA Binding Data Data Set Development Disease Disease Progression Enzymes Gene Activation Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genetically Engineered Mouse Genomics Glycolysis Glycolysis Pathway Goals Growth Hormones In Vitro Left Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Maps Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Metabolism Modeling Molecular Mus Oncogenic Outcome Pathway interactions Patients Pharmacology Phenotype Primary Neoplasm Prognosis Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins RNA Splicing Receptor Signaling Regulator Genes Research Resistance Role Sampling Side Signal Transduction Site TP53 gene Terminal Disease Testing Therapeutic Translating Treatment Failure Tumorigenicity VCaP Validation Variant Warburg Effect YY1 Transcription Factor Zinc Fingers advanced prostate cancer base castration resistant prostate cancer cell growth clinically relevant cofactor cohort enzyme pathway experimental study improved in vivo Model inhibitor innovation insight knock-down loss of function metabolomics mouse model novel novel strategies novel therapeutic intervention novel therapeutics overexpression programs prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer progression prostate carcinogenesis recruit standard care targeted agent therapy development therapy resistant transcription factor transcriptome sequencing treatment strategy tumor tumor metabolism

展开

项目摘要

PROJECT SUMMARY/ABSTRACT Standard treatment of prostate cancer with current agents fails due to development of therapy resistance and castration-resistant prostate cancer (CRPC), a terminal disease. CRPC differs from early-staged prostate cancer in its increased reliance on glycolysis (the Warburg effect) as well as emergence of therapy resistance due to the androgen receptor (AR) splice variant 7 (AR-V7), a truncated, constitutively active AR that mediates oncogenic programs in a hormone-independent manner. However, mechanisms underlying altered metabolism and AR-V7-incuded signaling in CRPC remain largely unclear. Our analyses of tumor versus paired normal samples uncovered overexpression of YY1, a zinc-finger transcription factor, during progression of CRPC. By genomic profiling (ChIP-seq and RNA-seq) in CRPC cells, we demonstrate that YY1 binds to and induces high transcription of metabolic genes such as PFKP, a rate-limiting enzyme for glycolysis. Loss-of-function and rescue studies show a YY1-PFKP axis essential for sustaining glycolysis and malignant growth of CRPC in cell models. Additionally, YY1 interacts with AR-V7 co-occupying a majority of AR-V7 targets, where combined actions of AR-V7 and YY1 maintain oncogenic signaling. Mass spectrometry-based identification of YY1 interactome uncovered YY1’s partners including bromodomain proteins. Knockdown of YY1, or blockade of bromodomain proteins, suppressed CRPC growth. We hypothesize that YY1 and AR-V7 act in concert to sustain both tumor metabolism (glycolysis)-related and AR-V7-related gene-expression programs, thereby producing more aggressive tumor phenotypes and therapy resistance in terminal CRPCs; we also hypothesize that targeting YY1’s co-activators reverses oncogenic signaling, providing an attractive anti-CPRC therapeutic. Dissecting the molecular mechanisms underlying the YY1-mediated CRPC progression should provide critical insights into new treatment strategies. Towards this goal, we will use additional models to further define the YY1:AR-V7 co-targeted gene pathways in CRPC; validation of this finding with primary tumor samples will be paradigm-shifting and change current views regarding how oncogenic signaling is wired in CRPC (Aim 1). We will define YY1 as a new oncogenic factor in promoting CRPC formation and tumor cell metabolism with cell and murine models (Aim 2). Lastly, we will determine blockade of YY1-associated co-activator machinery as new means for treatment of CRPC (Aim 3). Because certain glycolysis pathway enzymes and YY1 cofactors are potentially druggable with inhibitors, completion of the proposed research should not only promote a new mechanistic understanding of CRPC but will yield innovative therapeutics for treatment of affected patients.

项目摘要/摘要由于耐药性的发展和抗cast割前列腺癌（CRPC），一种终末疾病。 CRPC与早期前列腺不同癌症在增加对糖酵解的依赖（沃伯格效应）以及耐药性紧急由于雄激素受体（AR）剪接变体7（AR-V7），一种截短的组成性AR，介导与马无关的致癌程序。但是，新陈代谢改变的机制 CRPC中的AR-V7信号传导仍然在很大程度上不清楚。我们对肿瘤与配对正常的分析在CRPC进展过程中，样品发现了YY1（锌指转录因子）的过表达。经过 CRPC细胞中的基因组分析（CHIP-SEQ和RNA-SEQ），我们证明YY1与高高结合并诱导高代谢基因（例如PFKP）的转录，PFKP是一种用于糖酵解的速率限制酶。功能丧失和救援研究表明，YY1-PFKP轴可维持CRPC在细胞中的糖酵解和恶性生长至关重要型号。此外，YY1与AR-V7相互作用，将大多数AR-V7靶标共同占领 AR-V7和YY1的作用保持致癌信号传导。基于质谱的YY1鉴定互动揭示了YY1的合作伙伴，包括溴生型域蛋白。 yy1的敲除或溴结构域蛋白，抑制了CRPC生长。我们假设YY1和AR-V7共同行动维持肿瘤代谢（糖酵解）相关和与AR-V7相关的基因表达程序，从而在末端CRPC中产生更具侵略性的肿瘤表型和耐药性；我们也假设靶向YY1共激活因子的那个逆转致癌信号传导，提供了一种有吸引力的抗CPRC疗法。剖析YY1介导的CRPC进展的分子机制应提供关键洞悉新的治疗策略。为了实现这一目标，我们将使用其他模型进一步定义 YY1：AR-V7在CRPC中靶向基因途径；用原发性肿瘤样品对此发现的验证将是范式转移并改变有关如何在CRPC中连接致癌信号传导的当前观点（AIM 1）。我们将YY1定义为促进CRPC形成和肿瘤细胞代谢的一种新的致癌因子和鼠模型（AIM 2）。最后，我们将确定YY1相关的共激活器机械的封锁为治疗CRPC的新手段（AIM 3）。因为某些糖酵解途径酶和YY1辅助因子可能会被抑制剂吸毒，拟议研究的完成不仅应促进新的对CRPC的机械理解，但将产生创新的治疗治疗患者。