HOTAIR调控的高甲基化基因SIX3靶向AurA/B影响胶质瘤细胞有丝分裂的作用机制研究

表观遗传异常是肿瘤一个重要特征，我们前期证实SIX3为脑胶质瘤新高甲基化基因。研究发现HOTAIR抑制SIX3表达，干扰HOTAIR导致SIX3启动子区EZH2等聚集减少，H3K27me3水平降低。此外，证实ZNF263是SIX3的转录抑制因子，干扰ZNF263则降低SIX3基因启动子甲基化水平。综上提出科学假说：“HOTAIR通过ZNF263 靶向SIX3, 招募PRC2等影响组蛋白修饰，调控脑胶质瘤中SIX3的高甲基化修饰和表达”。同时发现AurkA/B是SIX3的靶基因，参与细胞有丝分裂。因此提出“SIX3作为转录因子负性调控AurkA/B表达，参与胶质瘤细胞的有丝分裂”。通过本项目研究，不仅可以阐明SIX3在胶质瘤中发生高甲基化修饰的机制，而且可以明确SIX3作为胶质瘤抑瘤基因的功能机制；同时也可以初步阐明LncRNA HOTAIR通过SIX3基因影响胶质瘤细胞有丝分裂的作用机制。

Epigenetic abnormalities are central to many common human diseases, including cancer. We previously demonstrated SIX3 is a new hypermethylated gene in glioma. and found lncRNA HOTAIR inhibits the expression of SIX3. Interference the expression of HOTAIR reduces EZH2 gathering in the promoter region of SIX3, which reducing the level of H3K27me3. In addition, we also confirmed that ZNF263 is transcription repressors of SIX3, and interference ZNF263 derceased the methylation of SIX3 promoter. We further discovered the interaction between HOTAIR and ZNF263. Based on these empirical and literature analysis, we hypothesize that “HOTAIR recruits PRC2 to target SIX3 through binding with ZNF263, leading to the hypermethylation of SIX3 in glioma”. We also found AurkA and AurkB are targets of SIX3, which are closely related with mitosis and genomic instability. In this project, we will elucidate not only the mechanism of SIX3 hypermethylation, but also the tumor suppressive function of SIX3 in glioma. Simultaneously, this project might preliminary clarify the mechanism of HOTAIR affected cell mitosis by regulating SIX3 gene in glioma.