Lei Yinrui, Chen Tao, Li Yeyi, Shang Man, Zhang Yan, Jin Yuepeng, Yu Qiujing, Guo Fang, Wang Ting
Department of Pharmacology And Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
Oncogenesis. 2020 Feb 14;9(2):21. doi: 10.1038/s41389-020-0208-1.
The protein O-GlcNAcylation catalysed by O-GlcNAc transferase (OGT) is tightly regulated by glucose availability. It is upregulated and essential for tumor cell proliferation under hypoxic conditions. However, the mechanism behind is still unclear. Here, we showed that the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), which also promotes cell cycle progression in the nucleus, was O-GlcNAcylated in response to hypoxia. The O-GlcNAcylation of PFKFB3 could compete phosphorylation by hypoxia-activated ERK at the same modification site Ser172. Phosphorylated PFKFB3 could interact with the protein G3BP2 and retain in the cytosol; this in turn led to the accumulation of hypoxia-induced-P27 in the nucleus resulting in the cell cycle arrest. Such a pathway was compromised by high level of PFKFB3 O-GlcNAcylation in tumor cells contributing to cell cycle progression. Consistently, the PFKFB3-Ser172 phosphorylation level inversely correlated with the OGT level in pancreatic cancer patients. Our findings uncovered an O-GlcNAcylation mediated mechanism to promote tumor cell proliferation under metabolic stress, linking the aberrant OGT activity to tumorigenesis in pancreatic cancer.
由O-连接的N-乙酰葡糖胺转移酶（OGT）催化的蛋白质O-连接的N-乙酰葡糖胺化受葡萄糖可用性的严格调控。在缺氧条件下，它会被上调，并且对肿瘤细胞增殖至关重要。然而，其背后的机制仍不清楚。在这里，我们表明糖酵解调节因子6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（PFKFB3），其也促进细胞核中的细胞周期进程，在缺氧时会发生O-连接的N-乙酰葡糖胺化。PFKFB3的O-连接的N-乙酰葡糖胺化可以在相同的修饰位点Ser172处竞争缺氧激活的ERK的磷酸化。磷酸化的PFKFB3可以与蛋白质G3BP2相互作用并保留在细胞质中；这反过来导致缺氧诱导的P27在细胞核中积累，从而导致细胞周期停滞。在肿瘤细胞中，高水平的PFKFB3 O-连接的N-乙酰葡糖胺化会破坏这种途径，从而促进细胞周期进程。一致地，在胰腺癌患者中，PFKFB3-Ser172的磷酸化水平与OGT水平呈负相关。我们的研究结果揭示了一种在代谢应激下促进肿瘤细胞增殖的O-连接的N-乙酰葡糖胺化介导的机制，将异常的OGT活性与胰腺癌的肿瘤发生联系起来。
