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
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do 31151, Republic of Korea.
Cancer Cell. 2017 Feb 13;31(2):208-224. doi: 10.1016/j.ccell.2017.01.003. Epub 2017 Feb 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, 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.
UBE2O定位于17q25位点，该位点在人类癌症中已知会发生扩增，但其在肿瘤发生中的作用仍不明确。在此我们表明，在MMTV-PyVT或TRAMP小鼠中删除Ube2o会严重损害肿瘤的起始、生长和转移，同时关闭肿瘤细胞的代谢重编程。从机制上讲，UBE2O特异性地靶向AMPKα2进行泛素化和降解，从而促进mTOR-HIF1α途径的激活。值得注意的是，AMPKα2而非AMPKα1的失活消除了由UBE2O缺失引起的肿瘤减弱，而用雷帕霉素治疗或抑制HIF1α则消除了UBE2O依赖性肿瘤生物学特性。最后，对UBE2O的药物阻断通过恢复AMPKα2来抑制肿瘤发生，表明UBE2O-AMPKα2轴是一个潜在的癌症治疗靶点。
