A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy.
A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy.
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DOI：
10.1016/j.ccell.2017.01.003
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发表时间：
2017-02-13
期刊：
影响因子：
50.3
通讯作者：
Song MS
中科院分区：
文献类型：
--
作者：
Vila IK;Yao Y;Kim G;Xia W;Kim H;Kim SJ;Park MK;Hwang JP;González-Billalabeitia E;Hung MC;Song SJ;Song MS
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. Vila et al. show that UBE2O, which is overexpressed in many human cancers, targets AMPKα2 for ubiquitination and degradation thereby promotes activation of the mTOR-HIF1α pathway. Genetic deletion or pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2.
