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O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia.
Oncogenesis ( IF 5.9 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41389-020-0208-1 Yinrui Lei 1, 2 , Tao Chen 3 , Yeyi Li 1 , Man Shang 1 , Yan Zhang 1 , Yuepeng Jin 4 , Qiujing Yu 5 , Fang Guo 2 , Ting Wang 1, 6
Oncogenesis ( IF 5.9 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41389-020-0208-1 Yinrui Lei 1, 2 , Tao Chen 3 , Yeyi Li 1 , Man Shang 1 , Yan Zhang 1 , Yuepeng Jin 4 , Qiujing Yu 5 , Fang Guo 2 , Ting Wang 1, 6
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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.
中文翻译：
缺氧条件下，肿瘤细胞增殖需要PFKFB3进行O-GlcNAcy化。
O-GlcNAc转移酶（OGT）催化的O-GlcNAcy蛋白质受葡萄糖利用率的严格调控。在缺氧条件下，它被上调并且对于肿瘤细胞增殖至关重要。但是，背后的机制仍不清楚。在这里，我们表明糖酵解调节剂6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶（PFKFB3），也促进细胞核在细胞周期中的进程，被O-GlcNAcycy响应缺氧。PFKFB3的O-GlcNAcylation可以与缺氧激活的ERK在相同的修饰位点Ser172上竞争磷酸化作用。磷酸化的PFKFB3可以与蛋白质G3BP2相互作用并保留在细胞质中。这又导致低氧诱导的P27在细胞核中积累，导致细胞周期停滞。肿瘤细胞中高水平的PFKFB3 O-GlcNAcylation破坏了这种途径，从而促进了细胞周期进程。一致地，胰腺癌患者中PFKFB3-Ser172的磷酸化水平与OGT水平呈负相关。我们的发现揭示了一种O-GlcNAcylation介导的机制，可促进代谢应激下肿瘤细胞的增殖，将异常的OGT活性与胰腺癌的肿瘤发生联系起来。
更新日期：2020-02-14
中文翻译：
缺氧条件下，肿瘤细胞增殖需要PFKFB3进行O-GlcNAcy化。
O-GlcNAc转移酶（OGT）催化的O-GlcNAcy蛋白质受葡萄糖利用率的严格调控。在缺氧条件下，它被上调并且对于肿瘤细胞增殖至关重要。但是，背后的机制仍不清楚。在这里，我们表明糖酵解调节剂6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶（PFKFB3），也促进细胞核在细胞周期中的进程，被O-GlcNAcycy响应缺氧。PFKFB3的O-GlcNAcylation可以与缺氧激活的ERK在相同的修饰位点Ser172上竞争磷酸化作用。磷酸化的PFKFB3可以与蛋白质G3BP2相互作用并保留在细胞质中。这又导致低氧诱导的P27在细胞核中积累，导致细胞周期停滞。肿瘤细胞中高水平的PFKFB3 O-GlcNAcylation破坏了这种途径，从而促进了细胞周期进程。一致地，胰腺癌患者中PFKFB3-Ser172的磷酸化水平与OGT水平呈负相关。我们的发现揭示了一种O-GlcNAcylation介导的机制，可促进代谢应激下肿瘤细胞的增殖，将异常的OGT活性与胰腺癌的肿瘤发生联系起来。
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