2. Academic Validation
  3. FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation

FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation

  • Nat Commun. 2019 Mar 27;10(1):1382. doi: 10.1038/s41467-019-09289-5.
Fei Yang 1 2,  Jie Xu 2,  Hua Li 2,  Mingjia Tan 2,  Xiufang Xiong 1,  Yi Sun 3 4
Affiliations

Affiliations

  • 1 Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China.
  • 2 Division of Radiation and Cancer Biology, Departments of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI, MI48109, USA.
  • 3 Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China. sunyi@umich.edu.
  • 4 Division of Radiation and Cancer Biology, Departments of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI, MI48109, USA. sunyi@umich.edu.
PMID: 30918250 DOI: 10.1038/s41467-019-09289-5
Abstract

FBXW2 inhibits proliferation of lung Cancer cells by targeting SKP2 for degradation. Whether and how FBXW2 regulates tumor invasion and metastasis is previously unknown. Here, we report that FBXW2 is an E3 Ligase for β-catenin. FBXW2 binds to β-catenin upon EGF-AKT1-mediated phosphorylation on Ser552, and promotes its ubiquitylation and degradation. FBXW2 overexpression reduces β-catenin levels and protein half-life, whereas FBXW2 knockdown increases β-catenin levels, protein half-life and transcriptional activity. Functionally, FBXW2 overexpression inhibits migration and invasion by blocking transactivation of MMPs driven by β-catenin, whereas FXBW2 knockdown promotes migration, invasion and metastasis both in vitro and in vivo Lung Cancer Models. In human lung Cancer specimens, while FBXW2 levels are inversely correlated with β-catenin levels and lymph-node metastasis, lower FBXW2 coupled with higher β-catenin, predict a worse patient survival. Collectively, our study demonstrates that FBXW2 inhibits tumor migration, invasion and metastasis in lung Cancer cells by targeting β-catenin for degradation.

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