Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress.
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.
Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Szu-Wei
SW
Lee
Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
Chien-Feng
CF
Li
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Guoxiang
G
Jin
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Zhen
Z
Cai
Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Fei
F
Han
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chia-Hsin
CH
Chan
Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Wei-Lei
WL
Yang
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bin-Kui
BK
Li
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abdol Hossein
AH
Rezaeian
College of Pharmacy, Department of Pharmacology and Toxicology, the University of Arizona, Tucson, AZ 85721, USA.
Hong-Yu
HY
Li
Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan.
Hsuan-Ying
HY
Huang
Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 404, Taiwan. Electronic address: hklin@mdanderson.org.
Hui-Kuan
HK
Lin
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000368:Aged; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002470:Cell Survival; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; C540569:CAB39 protein, human; D002135:Calcium-Binding Proteins; D044786:S-Phase Kinase-Associated Proteins; C476400:STRADA protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D018631:ras Proteins