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：
10276817
负责人：
Ling Cai
金额：
$ 44.31万
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10276817
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 Structure 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/antagonist 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

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.

项目概要/摘要由于治疗耐药性的发展和现有药物对前列腺癌的标准治疗失败去势抵抗性前列腺癌 (CRPC) 是一种与早期前列腺癌不同的晚期疾病。癌症对糖酵解（瓦尔堡效应）的依赖增加以及治疗耐药性的出现由于雄激素受体 (AR) 剪接变体 7 (AR-V7)，一种截短的、组成型活性 AR，介导然而，致癌程序以不依赖激素的方式进行。我们对肿瘤与配对正常细胞的分析在很大程度上仍不清楚。样本发现 YY1（一种锌指转录因子）在 CRPC 进展过程中过度表达。通过 CRPC 细胞中的基因组分析（ChIP-seq 和 RNA-seq），我们证明 YY1 结合并诱导高代谢基因的转录，例如 PFKP（一种糖酵解限速酶）和功能丧失。拯救研究表明 YY1-PFKP 轴对于维持细胞中 CRPC 的糖酵解和恶性生长至关重要此外，YY1 与 AR-V7 相互作用，共同占据大部分 AR-V7 目标。 AR-V7 和 YY1 的作用维持基于质谱的 YY1 致癌信号传导。相互作用组发现了 YY1 的伙伴，包括 YY1 的敲低或封锁。 bromodomain 蛋白，抑制 CRPC 生长，我们勇敢地说 YY1 和 AR-V7 协同作用。维持肿瘤代谢（糖酵解）相关和 AR-V7 相关基因表达程序，从而在终末 CRPC 中产生更具侵袭性的肿瘤表型和治疗耐药性；靶向 YY1 的共激活剂可逆转致癌信号，从而提供有吸引力的抗 CPRC 治疗。剖析 YY1 介导的 CRPC 进展的分子机制应该提供关键的信息为了实现这一目标，我们将使用其他模型来进一步定义新的治疗策略。 YY1：AR-V7 在 CRPC 中的共靶向基因通路；将用原发性肿瘤样本验证这一发现范式转变并改变关于 CRPC 中致癌信号如何连接的当前观点（目标 1）。将YY1定义为促进CRPC形成和肿瘤细胞代谢的新致癌因子和小鼠模型（目标 2），我们将确定 YY1 相关共激活剂机制的封锁为治疗 CRPC 的新方法（目标 3），因为某些糖酵解途径酶和 YY1 辅助因子。可能与抑制剂成药，完成拟议的研究不仅应该促进新的对 CRPC 的机制了解，但将为治疗受影响的患者产生创新的疗法。