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

Lee, Szu-Wei, Li, Chien-Feng, Jin, Guoxiang, Cai, Zhen, Han, Fei, Chan, Chia-Hsin, Yang, Wei-Lei, Li, Bin-Kui, Rezaeian, Abdol Hossein, Li, Hong-Yu, Huang, Hsuan-Ying, Lin, Hui-Kuan
Molecular cell 2015 v.57 pp. 1022-1033
carcinogenesis, cell viability, energy, hepatoma, therapeutics, ubiquitin-protein ligase, ubiquitination
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 in vivo. 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.