Understanding role of O-GlcNAcylation on cancer cell metabolism and survival

描述（由申请人提供）：乳腺癌是最常见的癌症类型，也是全球女性癌症相关死亡的最常见原因。目前还没有治愈乳腺癌的方法，因此对乳腺癌潜在生物学的更深入了解将确定分子靶点，并允许开发新的治疗方法。癌细胞表现出改变的代谢，其特征在于在有氧条件下增加的葡萄糖摄取和增加的糖酵解，这一过程被称为瓦尔堡效应。癌症依赖于代谢途径的确切分子机制尚不清楚。通过O-GlcNAc化、翻译后修饰调节蛋白质是取决于葡萄糖可用性的可逆过程，并且是调节蛋白质功能的有力机制。在这个提议中，我们将阐明营养传感器O-GlcNAc转移酶（OGT），负责催化O-GlcNAc添加到蛋白质的酶，如何调节癌细胞代谢和生存应激信号的机制。初步数据表明，O-GlcNAc酰化通过pVHL依赖性方式调节HIF-1调节癌症代谢。因此，我们假设O-GlcNAc化通过VHL依赖性的HIF-1？稳定化调节癌细胞代谢和生存应激信号。在目标#1中，我们将确定癌细胞存活的O-GlcNAc化调节是否需要ER应激和HIF-1？通路。在目标#2中，我们将确定O-GlcNAc的改变如何调节肿瘤抑制因子VHL蛋白，并确定其对O-GlcNAc介导的体外和体内癌细胞存活代谢和存活的调节的贡献。这些研究将 进一步了解癌细胞中的代谢重编程如何在分子水平上与生存应激途径联系起来，并确定新的抗癌途径。

DESCRIPTION (provided by applicant): Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. There is currently no cure for breast cancer and thus a greater understanding of the underlying biology of breast cancer will identify molecular targets and allow for the development of novel therapeutics. Cancer cells exhibit altered metabolism, characterized by increased glucose uptake and increased glycolysis under aerobic condition, a process known as Warburg effect. The exact molecular mechanisms underlying cancers dependency on metabolic pathways is unclear. Regulation of proteins by O- GlcNAcylation, post-translational modifications, is a reversible process that depends on glucose availability and is a powerful mechanism to regulate protein function. In this proposal, we will elucidate the mechanisms of how the nutrient sensor O-GlcNAc transferase (OGT), the enzyme responsible for catalyzing addition of O-GlcNAc to proteins, regulates cancer cell metabolism and survival stress signaling. Preliminary data suggests that O- GlcNAcylation regulates cancer metabolism via regulation of HIF-1¿ in a pVHL-dependent manner. Thus, we hypothesize that O-GlcNAcylation regulates cancer cell metabolism and survival stress signaling through VHL- dependent stabilization of HIF-1¿. In Aim #1, we will determine whether O-GlcNAcylation regulation of cancer cell survival requires ER stress and HIF-1¿ pathways. In Aim #2 we will determine how alterations in O- GlcNAc regulate the tumor suppressor VHL protein and determine its contribution to O-GlcNAc-mediated regulation on cancer cell survival metabolism and survival in vitro and in vivo. These studies will further our understanding of how metabolic reprogramming in cancer cells connects at the molecular level to survival stress pathways and identify novel anticancer pathways.