Uev1A facilitates osteosarcoma differentiation by promoting Smurf1-mediated Smad1 ubiquitination and degradation

Malignant bone tumor osteosarcoma (OS) displays high metastasis incidence and poor prognosis. Its stem cell properties could serve to explain tumor recurrence and resistance to conventional treatments. In this study, we identified UEV1A as a novel suppressor of OS. Elevated UEV1A diminishes stem cell properties of OS cells and drives them to terminal differentiation. Importantly, UEV1A-overexpressed OS cells delay proliferation and are more sensitive to chemotherapeutic agents than control cells. Uev1A appears to be involved in the BMP signaling pathway in which it collaborates with a ubiquitin E3 ligase Smurf1 to promote Smad1 degradation in a Ubc13-independent manner. Indeed, Smad1 is identified as a dominant downstream effector of Uev1A, which unravels the mechanism underlying Uev1A-orchestrated tumor suppression in OS. The above findings identify UEV1A as a potential OS tumor suppression gene, and shed lights to future OS diagnosis and treatment.