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SKP2-Driven Ubiquitination Regulates LKB1 Activity and HCC Tumor Growth

DOI: 10.1158/2159-8290.CD-RW2015-046 Published April 2015
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  • Major finding: SKP2-mediated ubiquitination is required for LKB1 activity and cell survival under metabolic stress.

  • Mechanism: K63-linked polyubiquitination is induced by oncogenic RAS and maintains LKB1 complex integrity.

  • Impact: Inhibition of SKP2 may enhance the sensitivity of liver cancer cells to metabolic drugs.

Although LKB1 (also known as serine/threonine kinase 11) has been implicated as a tumor suppressor, it may also have pro-oncogenic functions. LKB1 forms a heterotrimeric complex with STE20-related kinase adaptor α (STRAD) and calcium binding protein 39 (CAB39, also known as MO25) and activates AMP-activated protein kinase (AMPK) to conserve energy and protect cells from apoptosis under conditions of metabolic stress; however, the mechanisms that regulate LKB1 activity and its role in tumor progression are poorly understood. Lee and colleagues found that knockdown of S-phase kinase-associated protein 2 (SKP2), a component of the SKP1/Cullin/F-box (SCF) E3 ubiquitin ligase, impaired phosphorylation of AMPK, indicating that SKP2 is necessary for LKB1 activation. SKP2 directly interacted with LKB1 and induced Lys63 (K63)-linked polyubiquitination of the LKB1 N-terminus, which did not affect LKB1 stability but was required for its kinase activity. Mechanistically, SKP2-mediated polyubiquitination of LKB1 enhanced its binding to MO25 and stabilization of the LKB1–STRAD–MO25 complex. Moreover, oncogenic RAS promoted assembly of the SKP2–SCF complex and resulted in enhanced K63-linked polyubiquitination of LKB1 and activation of LKB1/AMPK signaling, thereby demonstrating that RAS is an upstream regulator of the LKB1/AMPK axis. Expression of wild-type LKB1, but not a ubiquitination-deficient LKB1 mutant, protected cells from metabolic stress–induced cell death and accumulation of defective mitochondria. In human patients with hepatocellular carcinoma (HCC), LKB1 and SKP2 were upregulated, overexpressed in late-stage disease, and independently correlated with poor survival outcome. In addition, overexpression of wild-type LKB1, but not ubiquitination-deficient or kinase-dead LKB1 mutants, promoted HCC tumor growth in vivo. This study identifies SKP2 as an important regulator of LKB1 activation in RAS-driven cancers and suggests that LKB1 is oncogenic in HCC. Furthermore, pharmacologic SKP2 inhibition may improve response rates to metabolic drugs in HCC and other RAS-driven cancers.

Lee SW, Li CF, Jin G, Cai Z, Han F, Chan CH, et al. SKP2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol Cell 2015 Feb 26 [Epub ahead of print].

  • ©2015 American Association for Cancer Research.
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Cancer Discovery: 5 (4)
April 2015
Volume 5, Issue 4
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SKP2-Driven Ubiquitination Regulates LKB1 Activity and HCC Tumor Growth
Cancer Discov April 1 2015 (5) (4) OF9; DOI: 10.1158/2159-8290.CD-RW2015-046

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SKP2-Driven Ubiquitination Regulates LKB1 Activity and HCC Tumor Growth
Cancer Discov April 1 2015 (5) (4) OF9; DOI: 10.1158/2159-8290.CD-RW2015-046
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