AURKB介导的组蛋白H3S10磷酸化调控E2F2基因表达促进肺癌细胞异常增殖的分子机制研究

Phosphorylation of histone H3 Ser10 (H3S10ph) by AURKB (Aurora kinase B) plays critical roles in the process of key life activities, such as mitosis, apoptosis, and DNA damage and repair pathways. However, the mechanisms underlying histone H3S10ph and gene transcriptional regulation remain largely unknown. This project is going to analyze the effects of H3S10ph mediated by AURKB on the aberrant proliferation of human lung cancer cells and related gene expression changes, histone modification communications, and signal transduction pathways, thus revealing a novel mechanism by which AURKB controls the development of lung cancer. Furthermore, this project is going to probe the novel recognition mode and characteristics of histone H3S10ph resolving the fine-tuned transcriptional regulation of key genes, such as E2F2, and to verify the biological roles of AURKB both in vitro and in vivo. In addition, we will screen the library of natural compounds for small molecule inhibitors of AURKB (AURKBi) and validate the efficacy of candidate small molecules. All these studies will strongly help rationalize AURKB as a potential ideal target for lung cancer therapy. The screening of AURKBi will also provide good candidate small molecules for drug develpoment for lung cancer.

极光激酶AURKB催化组蛋白H3 Serine10磷酸化(H3S10ph)，参与细胞有丝分裂、细胞凋亡和DNA损伤修复等重要生命活动过程。然而，多年来关于组蛋白H3S10ph修饰调控基因转录的分子机制并不清楚。本项目拟应用人肺癌细胞为研究对象，系统分析AURKB介导的H3S10ph对肺癌细胞异常增殖的影响与基因表达变化、组蛋白修饰标记相互关联以及相关信号通路的关系，揭示AURKB对肺癌发生发展的新调节机制。在此基础上，进一步解析组蛋白H3S10ph的识别新特征，探明E2F2等关键蛋白基因表达的精细调控过程并进行体内、体外实验验证。此外，利用天然产物化合物库初步筛选靶向AURKB小分子抑制剂并进行效能鉴定。该研究将深层次阐明AURKB介导的H3S10ph促进肺癌发生发展的分子机理，为筛选特异靶向AURKB的小分子抑制剂并进行肺癌的临床治疗提供有力理论依据。

极光激酶AURKB催化组蛋白H3 Serine10磷酸化(H3S10ph)，参与细胞有丝分裂、细胞凋亡和DNA损伤修复等重要生命活动过程。然而，多年来关于组蛋白H3S10ph修饰调控基因转录的分子机制并不清楚。本项目拟应用人肺癌、胃癌细胞为研究对象，系统分析AURKB介导的H3S10ph对肺癌细胞异常增殖的影响与基因表达变化、组蛋白修饰标记相互关联以及相关信号通路的关系，揭示AURKB对肺癌、胃癌发生发展的新调节机制。在此基础上，进一步解析组蛋白H3S10ph的识别新特征，探明E2F2、CCND1等关键蛋白基因表达的精细调控过程并进行体内、体外实验验证。该研究将深层次阐明AURKB介导的H3S10ph促进肺癌、胃癌发生发展的分子机理，为筛选特异靶向AURKB的小分子抑制剂并进行癌症的临床治疗提供有力理论依据。