转录因子YY2在肿瘤细胞谷氨酰胺代谢调控中的生物学机制研究

Yin Yang 2 (YY2) is a member of Yin Yang (YY) family; however, although it has a high similarity with Yin Yang 1 (YY1), which had been reported to regulate various biological pathways, little was known regarding the functions of YY2. Very recently, we and other groups have showed that in tumorigenesis, YY2 could indeed act in a contrary way with YY1, which had been known as an oncogene. YY2 could suppress tumor cells proliferation, and its expression is aberrantly low in tumor tissues compared to normal ones. However, the mechanism of YY2 in regulating tumorigenesis remains unclear. Glutamine metabolism is one of the most important characteristics of tumor cells, as it could provides tumor cells with energy as well as materials for biomacromolecules synthesis, both of them are critical for tumor cells high-rate proliferation. Glutamine metabolism could also suppress reactive oxygen species (ROS) level, and thus increase tumor cells anti-oxidative potential. Despite of its importance, the regulatory mechanism of tumor cells glutamine metabolism has not been clearly elucidated. In our preliminary study, we have revealed that YY2-silencing could significantly increase intracellular glutamine level in hepatocarcinoma cells and suppress ROS level. These findings indicate that YY2 might be a novel regulator of hepatocarcinoma cells glutamine metabolism, and that YY2 might suppress hepatocarcinoma cells proliferation by inhibiting their glutamine metabolism. However, the detail mechanism regarding YY2 regulation on hepatocarcinoma cells glutamine metabolism remains to be elucidated. Accordingly, in this project, we aim to: (1) reveal the role of YY2 in regulating the hepatocarcinoma cells glutamine metabolism; (2) elucidate the molecular mechanism of YY2 regulation on hepatocarcinoma cells glucose metabolism; (3) unravel the roles of YY2/glutamine metabolism pathway in regulating the proliferation and cell survival potentials of hepatocarcinoma cells, and subsequently, in promoting tumorigenesis. This study will not only unravel the novel roles and molecular mechanisms of YY2 in tumorigenesis, but also will provide new perspective regarding tumor cells glutamine metabolism.

转录因子Yin Yang 2（YY2）是阴阳因子家族的成员。目前研究发现YY2能抑制肿瘤细胞增殖，在肿瘤组织中呈低表达；然而其在肿瘤代谢调控中的作用机制尚未清楚。谷氨酰胺代谢途径为肿瘤细胞快速增殖提供必需的能量和物质，同时也能促进肿瘤细胞抗氧化能力，从而提高肿瘤细胞的生存率。课题组前期实验结果表明，YY2敲减能显著促进肝癌细胞胞内谷氨酰胺的积累并抑制胞内活性氧的水平，提示了YY2可能通过负调控谷氨酰胺代谢抑制肿瘤发生，然而YY2对肝癌细胞谷氨酰胺代谢的调控机制尚待深入探讨。本项目拟从以下三方面展开研究：（1）揭示YY2对肝癌细胞谷氨酰胺代谢功能的影响；（2）阐明YY2对肝癌细胞谷氨酰胺代谢的分子调控机制；（3）探讨YY2/谷氨酰胺代谢通路在调控肝癌细胞增殖和生存能力中的作用机制。本项目研究将揭示YY2在调控肿瘤发生发展中的新作用机制，同时也为肿瘤细胞谷氨酰胺代谢研究提供新的理论基础。

转录因子Yin Yang 2（YY2）是阴阳因子家族的重要成员。研究发现YY2能抑制肿瘤细胞增殖，在肿瘤组织中呈低表达；然而目前其在肿瘤代谢调控中的作用机制尚未清楚。氨基酸代谢重编程能为肿瘤细胞快速增殖提供必需的能量和物质，同时能促进肿瘤细胞抗氧化能力，提高微环境下肿瘤细胞的增殖生存。通过本项目的开展，课题组已取得如下研究成果：（1）本项目首次揭示了锌指蛋白YY2抑制谷氨酸-胱氨酸交换转运效率从而降低肿瘤细胞中谷胱甘肽（GSH）的合成、诱发铁死亡，最终抑制肿瘤发生发展。本项目研究揭示了YY2抑制肿瘤发生发展的一个新机制。（2）我们发现YY2可通过抑制铁死亡信号调控因子SLC7A11的转录活性，降低肿瘤细胞内GSH水平，导致肿瘤细胞对铁死亡的耐性下降，诱发肿瘤细胞铁死亡。这一新调控机制的发现加深了我们对细胞铁死亡分子调控机制的理解。（3）本项目研究揭示YY2能与另一个YY家族因子YY1竞争性结合SLC7A11 启动子。我们发现，YY1能促进SLC7A11的转录活性，因此YY1与YY2在调控SLC7A11表达方面起到截然相反的作用。这些研究结果提示了YY家族平衡的重要性，同时也揭示了YY1和YY2对肿瘤发生发展起到相反作用的分子机制。（4）本项目同时还发现YY2可通过抑制谷氨酰胺酶GLS1的表达从而抑制肿瘤细胞内谷氨酰胺的分解，在肿瘤发生发展中发挥重要的抑制功能。（5）本项目研究也发现YY2可以通过抑制丝氨酸代谢途径中PHGDH因子的转录活性，阻碍肿瘤细胞丝氨酸的合成，从而影响肿瘤细胞还原剂水平和核苷酸水平，最终抑制肿瘤的发生发展。综上所述，本项目研究阐明了YY2通过调控肿瘤细胞氨基酸代谢重编程发挥其抑制肿瘤的重要作用，揭示了YY2抑制肿瘤发生发展的新调控机制，为基于YY家族的肿瘤治疗新方法奠定了理论依据，同时也为肿瘤细胞谷氨酰胺代谢和细胞铁死亡研究提供新的理论基础。