乳腺癌中YY1调节促癌蛋白活性的机制及其应用价值的研究

Ying Yang 1 (YY1) 是重要的表观遗传学调节因子。我们和其他研究者的发现, YY1在乳腺癌中高表达并与病人的不良预后正相关；YY1通过其OPB区域结合并刺激促癌蛋白EZH2，MDM2和AKT；基于OPB的肽段抑制乳腺癌细胞增殖。因此我们假想：乳腺癌中YY1通过OPB区域调节一个或多个促癌信号通路，阻碍这种调节将成为癌症治疗的新方法。.鉴定这些假想的三个研究目标是：1. 用基因突变和细胞学方法研究YY1调节EZH2，MDM2和AKT的差异性和相对重要性，2. 用细胞学方法和动物模型剖析用OPB肽段阻遏YY1-促癌蛋白结合对乳腺癌的影响及发挥作用的最佳亚细胞空间，3. 分析OPB肽段与促癌蛋白抑制剂是否可以协同抑制乳腺癌。本项目将阐明YY1通过OPB区域调节三个促癌蛋白的相对重要性，为创新乳腺癌治疗方法提供理论依据。我们的终极目标是解析乳腺癌致病的调控机制，并将其应用于临床治疗。

Yin Yang 1 (YY1) is an important regulator of epigenetics. We and others discovered that YY1 is overexpressed in breast cancer and its increased expression correlated to poor prognoses of breast cancer patients. YY1 interacts with oncoproteins EZH2, MDM2 and AKT through its OPB (oncoprotein binding) domain and promotes their oncogenic activity. Peptides derived from the OPB sequence inhibits the proliferation of breast cancer cells. Based on these observations, we hypothesize that YY1 regulates one or more oncogenic signaling pathways in breast cancer and blocking this regulation represents a novel therapeutic approach in breast cancer therapies. ..To test these hypotheses, we designed three specific aims. In Aim 1, we will dissect the differential regulation of YY1-regulated EZH2, MDM2 and AKT oncogenic pathways and determine which pathway(s) is crucial to the development of breast cancer. We will employ the approaches of gene mutagenesis and cell-based assays. In Aim 2, we will study the effects of blocking the interaction of YY1-oncoproteins by OPB-based peptides on tumor formation and determine the subcellular localization of this inhibition. In Aim 3, we will investigate whether the OPB-based peptide and individual inhibitors of these oncoproteins may have synergistic inhibitory effect on breast cancer cells. ..This project will determine the relative importance of YY1-regulated oncogenic signaling pathways and provide theoretically support to the development of novel therapeutic approaches for breast cancer treatment. Our ultimate goal is to dissect the regulatory mechanisms of breast cancer development and progression, and apply our discoveries to the clinical application.