The Role of YY1 in Castration-Resistant Prostate Cancer

项目摘要/摘要 目前使用药物治疗前列腺癌的标准治疗失败是由于治疗耐药性和 耐阉割前列腺癌(CRPC)，一种晚期疾病。慢性前列腺癌不同于早期前列腺癌 癌症对糖酵解的依赖(沃堡效应)以及治疗耐药的出现 由于雄激素受体(AR)剪接变异体7(AR-V7)，一种截短的、结构性活性的AR介导 以激素不依赖的方式进行致癌计划。然而，代谢改变的潜在机制 而AR-V7在CRPC中所含的信号在很大程度上仍不清楚。我们对肿瘤与配对正常的分析 样本发现，在CRPC的进展过程中，锌指转录因子YY1过表达。通过 在CRPC细胞中的基因组图谱(ChIP-seq和rna-seq)，我们证明了YY1结合并诱导高 代谢基因的转录，如糖酵解的限速酶PFKP。功能丧失和 救援研究表明，YY1-PFKP轴对于维持糖酵解和细胞内CRPC的恶性生长是必不可少的 模特们。此外，YY1与AR-V7相互作用，共同占据了AR-V7的大部分目标 AR-V7和YY1的作用维持致癌信号。YY1的质谱学鉴定 互作组发现了包括溴结构域蛋白在内的YY1‘S伙伴。取消YY1，或封锁 溴域蛋白，抑制CRPC的生长。我们假设YY1和AR-V7协同作用 维持与肿瘤代谢(糖酵解)相关和AR-V7相关的基因表达计划，从而 在晚期CRPC中产生更具侵袭性的肿瘤表型和治疗耐药性；我们还假设 靶向YY1的S共激活子逆转了致癌信号，提供了一种有吸引力的抗CPRC治疗方法。 剖析YY1介导的CRPC进展的分子机制应该提供关键的 洞察新的治疗策略。为了实现这一目标，我们将使用其他模型来进一步定义 YY1：在CRPC中AR-V7共靶向基因通路；这一发现将在原发肿瘤样本中得到验证 转变范式和改变目前关于致癌信号如何在CRPC中连接的观点(目标1)。我们 将YY1定义为促进CRPC形成和肿瘤细胞与细胞代谢的新致癌因子 和小鼠模型(目标2)。最后，我们将确定对YY1相关共激活机制的封锁为 治疗慢性前列腺癌的新方法(目标3)。因为某些糖酵解途径的酶和YY1辅因子 都有可能与抑制剂一起下药，完成拟议的研究不仅应该促进一种新的 从机理上理解CRPC，但将产生治疗受影响患者的创新疗法。

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.