A UBE2O-AMPK alpha 2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

作者：Vila Isabelle K; Yao Yixin; Kim Goeun; Xia Weiya; Kim Hyejin; Kim Sun Joong; Park Mi Kyung; Hwang James P; Gonzalez Billalabeitia Enrique; Hung Mien Chie; Song Su Jung; Song Min Sup

来源：Cancer Cell, 2017, 31(2): 208-224.

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 AMPK alpha 2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1 alpha pathway. Notably, inactivation of AMPK alpha 2, but not AMPK alpha 1, abrogates the tumor attenuation caused by UBE2O loss, while treatment with rapamycin or inhibition of HIF1 alpha ablates UBE2O-dependent tumor biology. Finally, pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPK alpha 2, suggesting the UBE2O-AMPK alpha 2 axis as a potential cancer therapeutic target.

• 出版日期2017-2-13
• 单位中国医科大学