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

• Published in: Cancer cell 2017-02, Vol.31 (2), p.208-224
• Main Authors: Vila, Isabelle K., Yao, Yixin, Kim, Goeun, Xia, Weiya, Kim, Hyejin, Kim, Sun-Joong, Park, Mi-Kyung, Hwang, James P., González-Billalabeitia, Enrique, Hung, Mien-Chie, Song, Su Jung, Song, Min Sup
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - physiology; AMPK; AMPKα2; Animals; Antigens, Neoplasm - metabolism; arsenite; breast cancer; cancer metabolism; Disease Progression; HIF1α; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Life Sciences; Mice; Mice, Inbred C57BL; mTOR; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - etiology; prostate cancer; TOR Serine-Threonine Kinases - physiology; UBE2O; Ubiquitin-Conjugating Enzymes - antagonists & inhibitors; Ubiquitin-Conjugating Enzymes - physiology; Ubiquitination
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.01.003

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. [Display omitted] •Genetic ablation of Ube2o impairs progression of breast and prostate cancers in mice•UBE2O specifically targets AMPKα2 for ubiquitination and degradation•UBE2O-dependent tumor biology is mediated by mTOR and HIF1α•UBE2O blockade inhibits tumorigenesis through AMPKα2 restoration 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.