A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

Publication date: Available online 2 February 2017
Source:Cancer Cell
Author(s): Isabelle K. Vila, Yixin Yao, Goeun Kim, Weiya Xia, Hyejin Kim, Sun-Joong Kim, Mi-Kyung Park, James P. Hwang, Enrique González-Billalabeitia, Mien-Chie Hung, Su Jung Song, Min Sup Song
UBE2O is localized in the 17q25 locus, which is known to be amplified in human cancers, but its role in tumorigenesis remains undefined. Here we show that Ube2o deletion in MMTV-PyVT or TRAMP mice profoundly impairs tumor initiation, growth, and metastasis, while switching off the metabolic reprogramming of tumor cells. Mechanistically, UBE2O specifically targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Notably, inactivation of AMPKα2, but not AMPKα1, abrogates the tumor attenuation caused by UBE2O loss, while treatment with rapamycin or inhibition of HIF1α ablates UBE2O-dependent tumor biology. Finally, pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2, suggesting the UBE2O-AMPKα2 axis as a potential cancer therapeutic target.

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Teaser

Vila et al. show that UBE2O, which is overexpressed in many human cancers, targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Genetic deletion or pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2.


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