PKM2调控H2B泛素化修饰的分子机制及其在肿瘤代谢中的作用研究

Cancer metabolism is an increasing hot field in cancer research. The alternations in the metabolic levels or pathways are believed to be critical for tumorigenesis. Warburg Effect indicates, in tumor cells, the energy providing system was changed from mitochondrial oxidative phosphorylation to aerobic glycolysis. PKM2 catalyzes the last step of glycolysis, and is also a key regulator for Warburg Effect. To know whether epigenetic pathways are involved in the PKM2-regulated cancer metabolism and tumorigenesis, we performed a screen to determine the effect of PKM2 on histone modifications. We found that PKM2 down-regulates the levels of histone H2B monoubiquitination (H2Bub1). PKM2 interacts directly with H2B both in vitro and in vivo. Moreover, our results further suggest that loss of H2Bub1 promotes Warburg Effect significantly. Based on these original data, we will systematically study the molecular mechanisms of the regulation of H2Bub1 by PKM2, and roles of PKM2-H2Bub1 axis in the control of cancer metabolism and tumorigenesis. This project will provide significant contributions on the global understanding of the biological roles of H2Bub1, and dissect a novel pathway of PKM2 that involves epigenetics in the regulation of tumorigenesis. It is also valuable for the understanding of the mechanisms of tumorigenesis and cancer targeted molecule therapy.

肿瘤代谢是肿瘤研究的热点，代谢水平或途径的改变在肿瘤发生、发展中起着重要作用。与正常细胞不同，肿瘤细胞的能量主要由糖酵解供应，这一现象称为Warburg效应。PKM2是调控糖酵解最重要的限速酶，也是调控Warburg效应的关键蛋白。为了探讨表观遗传途径是否介导了PKM2的生物学功能，我们系统筛选了PKM2对组蛋白修饰的影响，发现PKM2显著抑制了H2B的泛素化水平。我们还发现PKM2与H2B有直接相互作用，抑制H2B泛素化修饰可以显著促进Warburg效应。我们将在这些工作的基础上，利用IP-WB、ChIP-seq以及肿瘤行为学等技术，进一步研究PKM2调控H2B泛素化的分子机制以及PKM2-H2B泛素化信号轴对肿瘤行为的影响及分子机制。本项目将拓宽人们对H2Bub1生物学功能的认识，阐明一条新的PKM2调控肿瘤的表观遗传途径，为理解肿瘤发病机理和开展肿瘤靶向治疗提供知识积累和理论依据。

代谢和表观遗传学是肿瘤学研究的两大热点，细胞代谢的重编程与细胞表观遗传学状态的改变之间存在密切联系，它们相互调节、相互影响，共同调控肿瘤的发生、发展。因此，深入研究肿瘤代谢和肿瘤表观遗传之间的相互关联，对全面理解肿瘤的发病机理和寻找新的肿瘤治疗靶标具有重要的理论意义和应用价值。本项目重点研究了肿瘤能量代谢重编程Warburg Effect与组蛋白修饰H2B泛素化（H2Bub1）之间的相互关联。研究结果表明，Warburg Effect的关键调控酶PKM2负调控H2Bub1的水平，而H2Bub1水平的下降又反过来通过表观遗传途径促进Warburg Effect和肿瘤细胞增殖。因此，本项目揭示了一条前所未知的、由PKM2-H2Bub1调控轴介导的表观遗传途径在调控肿瘤发生、发展中的重要作用及其分子机制，为开发新的肿瘤分子治疗策略提供了新的理论数据。