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. 2019 Jul;571(7763):127-131.
doi: 10.1038/s41586-019-1340-y. Epub 2019 Jun 26.

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

Xiongjun Wang  1   2   3 , Ruilong Liu  1   2 , Wencheng Zhu  1 , Huiying Chu  4 , Hua Yu  1   2 , Ping Wei  5 , Xueyuan Wu  6 , Hongwen Zhu  7 , Hong Gao  1   2 , Ji Liang  1   2 , Guohui Li  8 , Weiwei Yang  9   10
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UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis

Xiongjun Wang et al. Nature. 2019 Jul.

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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.

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