组蛋白去甲基化酶UTX在肺癌发病过程中的功能及其机制研究

Lung cancer has very high incidence and mortality, and is considered seriously endanger the national health in our country. During the development process of lung cancer, epigenetic changes such as histone methylation and de-methylation modification are known to play very important roles. Through bioinformatics analyses, we has found that the expression of UTX, a histone demethylase, is frequently down-regulated in human lung cancer samples. Moreover, we find that low UTX expression is significantly correlated with poor patient prognosis, indicating that UTX might play an important role in lung tumorigenesis. This project plans to combine the analyses of clinical lung cancer samples, human lung cancer cell lines as well as the de novo lung cancer mouse model to reveal the potential function of UTX in contributing to lung cancer development. Moreover, this project will uncover the underlying molecular mechanisms involving histone de-methylation through the integrative biochemical analyses and cell culture experiments. Lastly, this project will try to develop novel therapeutic strategies based on the translational studies in de novo mouse model. This project has generated several important progresses, especially the findings of the tumor promotion by the UTX knockout, which lay a solid foundation for further development of this project. This project will hopefully reveal the function and mechanism of histone demethylase UTX in the pathogenesis of lung cancer, and provide a better understanding of the epigenetic changes in contributing to lung tumorigenesis.

肺癌具有非常的高发病率和致死率，已经成为严重危害国民健康的重大疾病。在肺癌发生发展过程中，表观遗传学的改变包括组蛋白甲基化以及去甲基化修饰发挥着非常重要的作用。利用生物信息学分析方法，我们发现组蛋白去甲基化酶UTX的表达在肺癌临床样本中呈现普遍下调，并与患者的临床预后显著相关，提示其可能在肺癌发生发展中发挥着重要作用。本项目拟结合临床样本、人肺癌细胞株及原发肺癌小鼠模型深入地揭示UTX在肺癌发生发展过程中的功能，并进一步结合生化分析及细胞实验揭示UTX通过组蛋白去甲基化的修饰来调控肺癌发生发展的分子机制；在此基础上，将利用动物模型深入探讨针对UTX缺失的肺癌的治疗策略。本项目前期已经取得一些重要的阶段性进展，特别是发现UTX敲除能够显著地促进小鼠肺癌的发生发展，为本项目后续的深入开展奠定了坚实的工作基础。本项目将有希望揭示肺癌发病过程中组蛋白去甲基化酶UTX的功能及其作用机制，为深入理解肺癌发病相关的分子机制提供帮助。

本项目利用肺癌小鼠模型、肺癌细胞株以及临床样本资源整合性地研究组蛋白去甲基化酶UTX在肺癌发病过程中的功能及其机制。我们的主要研究发现包括：1）发现UTX缺失显著促进小鼠模型中肺癌的发生发展，鉴定UTX是新的肺癌抑癌基因；2）揭示UTX缺失后通过上调EZH2，导致H3K27me3水平升高，致使CDKN2A和CDKN2B等经典抑癌基因表达沉默，从而促进肺癌恶性进展的机制；3）发现EZH2的小分子抑制剂JQEZ5可作为UTX缺失型肺癌的潜在治疗策略。综上，我们的这项研究揭示了肺癌发病过程的表观调控新机制。项目资助期间项目负责人作为通讯或共同通讯作者在Nature Cancer、PNAS、National Science Review、Journal of Clinical Investigation等期刊发表项目标注论文20篇；申请专利4项，其中申请国际专利1项，国内专利3项；获得国内授权专利1项。