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：
10907068
负责人：
Ling Cai
金额：
$ 43.51万
依托单位：
DUKE UNIVERSITY
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 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10907068
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 LNCaP 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 Phenotype Primary Neoplasm Prognosis 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 Tumor Promotion Tumorigenicity VCaP Validation Variant Warburg Effect YY1 Transcription Factor Zinc Fingers advanced prostate cancer 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 pharmacologic 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 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.

项目摘要/摘要由于耐药性的发展和持续性前列腺癌（CRPC），一种终末疾病。癌症在增加对糖酵解的依赖（Warburg抗药性的出现）中由于雄激素受体（AR）剪接变体7（AR-V7），一种截短的，有效的AR介导但是，以激素方式进行致癌计划。和AR-V7的信号转导，剩余的较大尚不清楚。样品在CRPC的进展过程中发现了YY1（锌指转录因子）的过表达。 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。救援研究表明，AY1-PFKP轴可维持细胞中CRPC的糖酵解和恶性粒度至关重要此外，YY1与AR-V7相互作用 AR-V7和YY1的作用保持致癌信号。相互作用的YY1包括bromodomain蛋白。 Bromodomain蛋白抑制了CRPC的生长。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；靶向YY1的共激活因子逆转致癌信号传导，提供了有吸引力的抗CPRC治疗性。减轻YY1介导的CRPC进度的分子机制应提供关键洞悉新的治疗策略。 YY1：AR-V7在CRPC中共同靶向基因途径；范式转移和改变有关crpc的致癌信号传导的当前观点（AIM 1）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）。治疗CRPC的新手段（AIM 3）。可能会被抑制剂吸毒，拟议研究的组成不仅表明，不仅促进了新的对CRPC的机械理解，但将产生治疗患者的治疗剂。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Through the lens of phase separation: intrinsically unstructured protein and chromatin looping.

DOI：
10.1080/19491034.2023.2179766
发表时间：
2023-12
期刊：
Nucleus (Austin, Tex.)
影响因子：
0
作者：
通讯作者：

USP7 facilitates SMAD3 autoregulation to repress cancer progression in p53-deficient lung cancer.

DOI：
10.1038/s41419-021-04176-8
发表时间：
2021-09-27
期刊：
Cell death & disease
影响因子：
9
作者：
Huang YT;Cheng AC;Tang HC;Huang GC;Cai L;Lin TH;Wu KJ;Tseng PH;Wang GG;Chen WY
通讯作者：
Chen WY