Abstract
Ube2o deletion suppresses the growth of breast and prostate cancers and extends survival in mice.
Major finding: Ube2o deletion suppresses the growth of breast and prostate cancers and extends survival in mice.
Mechanism: UBE2O directly ubiquitinates AMPKα2 to promote its degradation and activate mTOR–HIF1α signaling.
Impact: UBE2O may be therapeutically targeted in cancer to restore AMPKα2 and inhibit tumorigenesis.
UBE2O is an E3-independent E2 ubiquitin-conjugating enzyme that is frequently amplified in cancer, but its role in tumorigenesis has not been fully elucidated. To better understand the role of UBE2O in vivo, Vila, Yao, and colleagues deleted Ube2o in a mouse model of breast cancer that metastasizes to the lung, resulting in delayed tumor onset, reduced tumor burden (with approximately half of mice not developing tumors at all), prevention of metastasis, and extended survival. Similar results were obtained in a mouse model of prostate cancer. The alpha-2 subunit of AMPK, a heterotrimeric serine/threonine kinase implicated in cancer cell survival, was identified as a UBE2O interacting protein by affinity purification mass spectrometry. UBE2O directly ubiquitinated AMPKα2, but not AMPKα1, thereby promoting its proteasomal degradation. Consistent with these findings, UBE2O depletion increased phosphorylation of AMPK substrates, and promoted AMPKα2-mediated suppression of the mTOR–HIF1α signaling pathway and metabolic reprogramming. Further, UBE2O depletion suppressed tumorigenesis only in the presence of AMPKα2, indicating that UBE2O mediates tumorigenesis via AMPKα2 degradation. UBE2O was highly expressed in breast tumors, and data from The Cancer Genome Atlas indicated that UBE2O was upregulated in approximately 20% of human breast, bladder, liver, and lung carcinomas. Moreover, high expression of UBE2O was associated with a poorer survival in patients with cancer. In addition, UBE2O expression was inversely correlated with AMPKα2 expression in human breast tumors, validating the in vitro findings. Based on these data a UBE2O inhibitor was tested in mouse models of breast and prostate cancers, and UBE2O inhibition reduced tumor incidence and progression and extended survival. Collectively, these results elucidate an oncogenic role for UBE2O in promoting mTOR–HIF1α signaling, and suggest that therapeutic targeting of UBE2O may restore AMPKα2 to suppress tumorigenesis.
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