Uev1A promotes breast cancer cell survival and chemoresistance through the AKT-FOXO1-BIM pathway

Abstract

AbstractBackgroundUbiquitin-conjugating enzyme variantUEV1Ais required for Ubc13-catalyzed K63-linked poly-ubiquitination that regulates several signaling pathways including NF-κB, MAPK and PI3K/AKT. Previous reports implicateUEV1Aas a potential proto-oncogene and have shown thatUEV1Apromotes breast cancer metastasis through constitutive NF-кB activation. Ubc13-Uev1A along with TARF6 can also ubiquitinate AKT but its downstream events are unclear.MethodsIn this study, we experimentally manipulatedUEV1expression in two typical breast cancer cell lines MDA-MB-231 and MCF7 under serum starvation conditions and monitored AKT activation and its downstream protein levels, as well as cellular sensitivity to chemotherapeutic agents.ResultsWe found that overexpression ofUEV1Ais sufficient to activate the AKT signaling pathway that in turn inhibitsFOXO1andBIMexpression to promote cell survival under serum starvation conditions and enhances cellular resistance to chemotherapy. Consistently, experimental depletion of Uev1 in breast cancer cells inhibits AKT signaling and promotes FOXO1 and BIM expression to reduce cell survival under serum starvation stress and enhance chemosensitivity.ConclusionsUev1A promotes cell survival under serum starvation stress through the AKT-FOXO1-BIM axis in breast cancer cells, which unveals a potential therapeutic target in the treatment of breast cancers.