阴阳因子YY1调控肿瘤糖酵解的代谢生物学机制研究

Currently, cancer is one of malignant diseases with the highest mortality. Cancer cells have various characteristics that differ from normal cells, and these hallmarks are important for development of effective cancer therapies. However, their detailed molecular mechanisms have not been fully understood. Recently, it has been reported that tumor microenvironment is a key factor that contributes to the tumor biological hallmarks. Due to their limitless proliferation, cancer cells are often located in a niche microenvironment where the supply of both oxygen and nutrients is insufficient. Cancer cells not only could survive and proliferate in the hypoxic conditions; rather, it has been known that the severity of the microenvironment positively correlates with the malignancies of tumors. Recent studies revealed that cancer metabolism is specific, and this specific metabolism provides them the basis for immortal biological hallmarks. Most cancer cells rely on glycolysis, not oxidative phosphorylation, to provide them the energy and other resources they need to proliferate in the hypoxic microenvironment. However, the mechanism controlling cancer metabolism remains to be deeply explored. Our previous study firstly showed that, in the hypoxic conditions, inhibition of Yin Yang 1 (YY1) significantly decreased the stability of hypoxia-inducible factor-1alpha (HIF-1alpha),leading to the decreased proliferation rate of cancer cells. Recently, it is reported that HIF-1alpha is important for regulating the expression of genes involved in cancer metabolism. We therefore postulate that YY1 is responsible for the regulation of cancer metabolism under the hypoxic conditions. The role of YY1 in cancer metabolism, particularly, whether YY1 is involved in the glycolysis pathway has not been reported yet. In this project, we will: 1) elucidate the molecular mechanism by which YY1 regulates the glycolysis pathway in cancer cells; 2) reveal the interrelationship between YY1 and other signaling molecules (e.g. HIF-1 and p53) and clarify their functional roles in glycolysis; and 3) validate the role of YY1 in glycolysis pathway by using mouse tumor models and clinical specimens from cancer patients. We ensure that this study will unravel the novel mechanism of cancer metabolism, and provide a new basis for cancer therapy by targeting genes involved in cellular adaptation to tumor microenvironments.

阴阳因子YY1是一个重要的生理病理学信号调控分子，因其既有抑制功能，也有激活功能, 所以被命名为阴阳因子。它不仅参与胚胎发育过程，而且也与肿瘤细胞增殖及其血管生成有着密切联系。既往研究表明肿瘤微环境影响其进化变异的生物学特性。其中，肿瘤糖酵解代谢被视为微环境下肿瘤生物学特性的基础之一。我们前期研究已发现，YY1能调控肿瘤微环境的关键信号分子HIF-1，影响肿瘤生长。但是，目前YY1是否参与肿瘤微环境下糖酵解代谢调控机制尚待深入探讨。本课题拟从以下三个方面展开研究：(1)解析YY1对肿瘤糖酵解代谢因子的调控机制；(2)理清YY1与HIF-1及p53信号之间的网络调控在肿瘤糖酵解代谢中的作用；(3)通过肿瘤动物模型并结合肿瘤患者样本，验证YY1对肿瘤糖酵解代谢分子调控以及代谢功能的影响。通过本项研究为肿瘤代谢生物学提供新的理论基础，也为肿瘤诊断及靶标分子治疗提供新的理论依据。

肿瘤细胞具有无限增殖、转移、肿瘤血管新生等各种特征，其中，代谢重编程是肿瘤细胞最基础的生物特性之一，肿瘤细胞通过改变其代谢通路促进各种生物大分子的合成。同时，肿瘤细胞往往也处于低氧微环境下，而代谢重编程能促进肿瘤细胞适应这种恶劣的微环境。阴阳因子YY1是一个具有高度保守的转录因子，研究预测分析表明YY1可调控约7%的哺乳动物基因。目前研究已报道YY1参与到DNA复制、胎儿发育、细胞分化等各种生理过程，且YY1表达在结肠癌、乳腺癌、膀胱癌等各种肿瘤中异常升高。我们的前期研究也表明了YY1可通过p53非依赖通路促进肿瘤细胞增殖、肿瘤血管新生以及肿瘤转移。然而，YY1是否参与肿瘤细胞代谢调控，是否通过调控肿瘤细胞代谢促进肿瘤发生发展尚未清楚，为阐明YY1在肿瘤细胞代谢中的调控机制，课题组展开了本项目研究。本项目中，课题组利用实时定量PCR、免疫印迹、免疫组化、染色质免疫共沉淀、报告基因等生化和分子生物学方法，以及动物实验和临床肿瘤组织分析，阐明了YY1在肿瘤发生发展的新作用机制：1）首次揭示了YY1通过p53非依赖途径调控肿瘤代谢戊糖磷酸通路的关键因子6-磷酸葡萄糖脱氢酶（G6PD），从而促进肿瘤细胞戊糖磷酸途径，增加生物大分子合成和清除活性氧促进肿瘤细胞增殖；2）阐明了YY1通过p53非依赖途径调控葡萄糖转运体3（GLUT3）转录调控，并证明了YY1通过增强肿瘤细胞葡萄糖摄取促进肿瘤细胞增殖；3）发现了YY1通过抑制PPARγ Coactivator-1beta（PGC1-beta）阻止脂肪酸beta-氧化和降解，揭示了YY1在低氧微环境促进肿瘤细胞脂质积累的调控机制，并证明了该机制对YY1在肿瘤细胞增殖中的关键性作用。综上所述，通过本项目研究，我们发现了YY1调控多种肿瘤细胞代谢通路的新功能，并将其在肿瘤发生发展的作用与肿瘤最基础的生物特征之一代谢重编程联系起来。这些发现不仅阐明了YY1在促进肿瘤发生发展分子调控机制中的多功能性，同时也提示了YY1有望成为肿瘤治疗分子靶标因子。

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