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

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 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.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • ELAV-Like Protein 1 / deficiency
  • ELAV-Like Protein 1 / genetics
  • ELAV-Like Protein 1 / metabolism
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / prevention & control*
  • Phosphotyrosine / metabolism
  • Prognosis
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Snail Family Transcription Factors / biosynthesis
  • Snail Family Transcription Factors / genetics*
  • Uridine Diphosphate Glucose / metabolism*
  • Uridine Diphosphate Glucose Dehydrogenase / chemistry
  • Uridine Diphosphate Glucose Dehydrogenase / genetics
  • Uridine Diphosphate Glucose Dehydrogenase / metabolism
  • Uridine Diphosphate Glucuronic Acid / metabolism


  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • RNA, Messenger
  • RNA, Neoplasm
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Phosphotyrosine
  • Uridine Diphosphate Glucuronic Acid
  • Uridine Diphosphate Glucose Dehydrogenase
  • Uridine Diphosphate Glucose