A UBE2O-AMPK?2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy.
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ABSTRACT:
SUBMITTER: Vila IK
PROVIDER: S-EPMC5463996 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy.
Vila Isabelle K IK Yao Yixin Y Kim Goeun G Xia Weiya W Kim Hyejin H Kim Sun-Joong SJ Park Mi-Kyung MK Hwang James P JP González-Billalabeitia Enrique E Hung Mien-Chie MC Song Su Jung SJ Song Min Sup MS
Cancer cell 20170202 2
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, ...[more]
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Project description: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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