A UBE2O-AMPKα2 axis that promotes tumor initiation and progression offers opportunities for therapy. Mus musculus

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. Overall design: In order to elucidate the pathophysiological impact of UBE2O loss, we generated mouse embryonic fibroblasts (MEFs), derived from day 13.5 embryos of C57BL6 mice, stably expressing control or Ube2o shRNA. We then performed microarray analysis in these cells. Three independent MEFs from each shRNA were analyzed. Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon UBE2O-loss.