Skp2-Dependent Ubiquitination and Activation of LKB1 Is Essential for Cancer Cell Survival under Energy Stress

Szu Wei Lee, Chien Feng Li, Guoxiang Jin, Zhen Cai, Fei Han, Chia Hsin Chan, Wei Lei Yang, Bin Kui Li, Abdol Hossein Rezaeian, Hong Yu Li, Hsuan Ying Huang, Hui Kuan Lin

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Abstract

LKB1 is activated by forming a heterotrimeric complex with STRAD and MO25. Recent studies suggest that LKB1 has pro-oncogenic functions, besides acting as a tumor suppressor. How the LKB1 activity is maintained and how LKB1 regulates cancer development are largely unclear. Here we show that K63-linked LKB1 polyubiquitination by Skp2-SCF ubiquitin ligase is critical for LKB1 activation by maintaining LKB1-STRAD-MO25 complex integrity. We further demonstrate that oncogenic Ras acts upstream of Skp2 to promote LKB1 polyubiquitination by activating Skp2-SCF ubiquitin ligase. Moreover, Skp2-mediated LKB1 polyubiquitination is required for energy-stress-induced cell survival. We also detected overexpression of Skp2 and LKB1 in late-stage hepatocellular carcinoma (HCC), and their overexpression predicts poor survival outcomes. Finally, we show that Skp2-mediated LKB1 polyubiquitination is important for HCC tumor growth invivo. Our study provides new insights into the upstream regulation of LKB1 activation and suggests a potential target, the Ras/Skp2/LKB1 axis, for cancer therapy.

Original languageEnglish (US)
Pages (from-to)1022-1033
Number of pages12
JournalMolecular cell
Volume57
Issue number6
DOIs
StatePublished - Mar 19 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Lee, S. W., Li, C. F., Jin, G., Cai, Z., Han, F., Chan, C. H., Yang, W. L., Li, B. K., Rezaeian, A. H., Li, H. Y., Huang, H. Y., & Lin, H. K. (2015). Skp2-Dependent Ubiquitination and Activation of LKB1 Is Essential for Cancer Cell Survival under Energy Stress. Molecular cell, 57(6), 1022-1033. https://doi.org/10.1016/j.molcel.2015.01.015