2. Academic Validation
  3. UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis

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.
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
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China.
  • 4 Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
  • 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 6 Department of Radiation Oncology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
  • 7 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 8 Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. ghli@dicp.ac.cn.
  • 9 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. wyang@sibcb.ac.cn.
  • 10 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. wyang@sibcb.ac.cn.
PMID: 31243371 DOI: 10.1038/s41586-019-1340-y
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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