Novel Posttranslational Modification in LKB1 Activation and Function

Cancer cells display dramatic alterations in cellular metabolism to meet their needs of increased growth and proliferation. In the last decade, cancer research has brought these pathways into focus, and one emerging issue that has come to attention is that many oncogenes and tumor-suppressors are intimately linked to metabolic regulation (Jones and Thompson, 2009). One of the key tumor-suppressors involved in metabolism is Liver Kinase B1 (LKB1). LKB1 is the major upstream kinase of the evolutionarily conserved metabolic sensor—AMP-activated protein kinase (AMPK). Activation of the LKB1/AMPK pathway provides a survival advantage for cells under energy stress. LKB1 forms a heterotrimeric complex and is activated through binding of the two regulatory proteins, STRAD and MO25. LKB1 has been shown to be a tumor-suppressor in various mouse models; however, recent studies suggest that LKB1 has pro-oncogenic functions. How the LKB1 activity and the LKB1-STRAD-MO25 complex are maintained and regulated and how LKB1 regulates cancer development are largely unclear. Here we show that K63-linked LKB1 polyubiquitination by the Skp1-Cul1-F-box-protein/Skp2 (Skp2-SCF) ubiquitin ligase complex is critical for LKB1 activation by a mechanism of maintaining the LKB1-STRAD-MO25 complex integrity. We further demonstrate that oncogenic Ras acts upstream of Skp2 to promote LKB1 polyubiquitination by activating the Skp2-SCF ubiquitin ligase complex. Moreover, Skp2-mediated LKB1 polyubiquitination is required for energy stress-induced cell survival. We also detected upregulation and positive correlation of Skp2 and LKB1 expression in late-stage hepatocellular carcinoma (HCC), and their overexpression predicts poor survival outcome of HCC patients. Finally, we show that Skp2-mediated LKB1 polyubiquitination is important for HCC tumor growth in a mouse subcutaneous xenograft tumor model. 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