Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress

Molecular Cell
Szu-Wei LeeHui-Kuan Lin

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 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.

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Citations

Feb 16, 2016·Seminars in Cell & Developmental Biology·Boris Y Shorning, Alan R Clarke
Nov 26, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Hui GuoFrancois X Claret
Dec 3, 2015·Future Medicinal Chemistry·John Kenneth MorrowShuxing Zhang
Oct 25, 2016·Biochimica Et Biophysica Acta·Ji ChengWenyi Wei
Dec 17, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Feng-Juan YanHongliang Li
Jul 1, 2017·Genes·Per HydbringLars-Gunnar Larsson
Oct 19, 2017·Cancer Metastasis Reviews·Dong WangWenyi Wei
Jul 16, 2016·Experimental & Molecular Medicine·Sang-Min Jeon
May 12, 2017·Journal of Tissue Engineering and Regenerative Medicine·Ping WangAbraham Schneider
Mar 1, 2020·G3 : Genes - Genomes - Genetics·Thanh Hung NguyenJan-Michael Kugler
Oct 22, 2015·Oncotarget·Chantal ThibertMarc Billaud
Sep 7, 2018·Scientific Reports·Guanghui WangJiajun Du
Mar 7, 2020·Signal Transduction and Targeted Therapy·Lu DengPing Wang
May 27, 2016·The Journal of Biological Chemistry·Ananthalakshmy SundararamanAnnapoorni Rangarajan
Aug 12, 2017·Leukemia & Lymphoma·Michal KulinskiShahab Uddin
Nov 30, 2019·Oxidative Medicine and Cellular Longevity·Francesco CiccareseStefano Indraccolo
Jun 14, 2020·Signal Transduction and Targeted Therapy·Ling ChenYongguang Tao
Nov 15, 2018·International Journal of Molecular Sciences·Yan YanKarsten Melcher
Jul 13, 2017·Molecular Oncology·Elisabeth Katharina TrappMarianna Alunni-Fabbroni
Mar 16, 2018·Oncogene·Lars Kullmann, Michael P Krahn
Jul 15, 2020·Nature Microbiology·Christin HerrmannMatthew D Weitzman
Sep 27, 2018·Molecular & Cellular Oncology·Szu-Wei Lee, Hui-Kuan Lin
Nov 21, 2019·Molecular Cancer Research : MCR·Adrian BuensucesoTrevor G Shepherd
Apr 17, 2020·Signal Transduction and Targeted Therapy·Lu DengPing Wang

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