State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Nature. 2019 Jul;571(7763):127-131. doi: 10.1038/s41586-019-1340-y. Epub 2019 Jun 26.
Cancer metastasis is the primary cause of morbidity and mortality, and accounts for up to 95% of cancer-related deaths. Cancer cells often reprogram their metabolism to efficiently support cell proliferation and survival. However, whether and how those metabolic alterations contribute to the migration of tumour cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid. Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine 473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R (HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL initiates the epithelial-mesenchymal transition, thus promoting the migration of tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour metastasis by increasing the stability of SNAI1 mRNA.
癌症转移是发病率和死亡率的主要原因，约占 95%与癌症相关的死亡。癌细胞经常重新编程其代谢以有效地支持细胞增殖和存活。然而，这些代谢变化是否以及如何促进肿瘤细胞的迁移在很大程度上仍然未知。UDP-葡萄糖 6-脱氢酶 (UGDH) 是戊糖酸途径中的关键酶，可将 UDP-葡萄糖转化为 UDP-葡萄糖醛酸。在这里，我们表明，在 EGFR 激活后，UGDH 在人类肺癌细胞中的酪氨酸 473 处发生磷酸化。磷酸化的 UGDH 与 Hu 抗原 R (HuR) 相互作用，并将 UDP-葡萄糖转化为 UDP-葡萄糖醛酸，从而减弱 UDP-葡萄糖介导的 HuR 与 SNAI1 mRNA 结合的抑制作用，从而增强 SNAI1 mRNA 的稳定性。SNAIL 的产生增加会引发上皮-间充质转化，从而促进肿瘤细胞的迁移和肺癌转移。此外，UGDH 在酪氨酸 473 处的磷酸化与肺癌患者的转移性复发和预后不良相关。我们的发现揭示了 UDP-葡萄糖在肺癌转移中的肿瘤抑制作用，并揭示了 UGDH 通过增加 SNAI1 mRNA 的稳定性促进肿瘤转移的机制。
