UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis

Xiongjun Wang, Ruilong Liu, Wencheng Zhu, Huiying Chu, Hua Yu, Ping Wei, Xueyuan Wu, Hongwen Zhu, Hong Gao, Ji Liang, Guohui Li () and Weiwei Yang ()
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Xiongjun Wang: University of the Chinese Academy of Sciences
Ruilong Liu: University of the Chinese Academy of Sciences
Wencheng Zhu: University of the Chinese Academy of Sciences
Huiying Chu: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Hua Yu: University of the Chinese Academy of Sciences
Ping Wei: Fudan University Shanghai Cancer Center
Xueyuan Wu: First Affiliated Hospital of Wenzhou Medical College
Hongwen Zhu: Chinese Academy of Sciences
Hong Gao: University of the Chinese Academy of Sciences
Ji Liang: University of the Chinese Academy of Sciences
Guohui Li: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Weiwei Yang: University of the Chinese Academy of Sciences

Nature, 2019, vol. 571, issue 7763, 127-131

Abstract: Abstract Cancer metastasis is the primary cause of morbidity and mortality, and accounts for up to 95% of cancer-related deaths1. Cancer cells often reprogram their metabolism to efficiently support cell proliferation and survival2,3. 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 acid4. 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.

Date: 2019
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DOI: 10.1038/s41586-019-1340-y

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