申请人前期研究发现：HOTAIR这个lncRNA与胶质瘤的分级、分型和预后相关，其5’功能结构域与PRC2复合物组分EZH2的结合是发挥HOTAIR功能、促进肿瘤无控性增殖的关键因素。本课题集中在“阻断HOTAIR功能结构域与PRC2结合的小分子化合物筛选与逆转肿瘤恶性表型”的方向。在结构模拟和分子对接的基础上获得候选化合物群，应用H3K27-NLK病毒报道系统和免疫沉淀、信号通路分析等方法，在细胞水平比较研究HOTAIR的5’功能结构域及其突变体对PRC2复合物的核募集调控作用、得到最优候选化合物；借助于信号通路分析、基因恢复实验、基因-蛋白质测序分析技术研究该化合物对Wnt下游信号通路的调控网络；最后利用裸鼠原位移植瘤模型研究候选小分子药物对肿瘤侵袭和转移的在体抑制作用。本研究对寻找lncRNA靶向小分子抑制剂的先导化合物具有指导意义，并具有临床转化潜在价值。

Non-coding RNA (ncRNA) are functional RNAs that do not encode proteins. NcRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), tRNAs, snoRNAs, and siRNAs. Different from miRNAs, lncRNAs generally comprise non-protein-coding RNAs that consist of more than 200 nucleotides. Recent reports have indicated that lncRNAs can serve as prognostic markers in various cancer types.We recently discovered that HOTAIR is a cell cycle-related lncRNA in human glioma, and its expression is closely associated with glioma staging and poor prognosis.We also demonstrated that the binding between 5’ functional domain of HOTAIR and EZH2 (component of PRC2 complex) is the key factor for HOTAIR induced uncontrollable growth of glioma cells. We mainly focus on “exploring small molecule inhibitor compounds blocking the formation of HOTAIR 5’ domain-EZH2 network and inhibiting malignant phenotypes of glioma cells” in this study. According to structural modeling and molecular docking, candidate compounds will be obtained. Firstly, H3K27-NLK virus reporting system will be introduced to compare the function of both wild type and mutant type of HOTAIR 5’ domain in recruiting PRC2 complex and to screen the best candidate compound in vitro. Secondly, signaling pathway investigation, gene restoration experiments, gene-protein sequencing analysis techniques will be performed to study the regulation network in Wnt signal downstream pathways of this compound. Finally, tumor invasion and metastasis inhibitory effects of this candidate compound will be examined in an orthotopic mice model.This study will be instructive for finding lncRNA targeted small molecule inhibitors, and has the potential to guide lncRNA based translational medicine research.