Abstract: FoxO transcription factors have been reported to play pivotal roles in tumorigenesis and drug resistance. The mechanistic insights underlying the tumor suppression function of FoxOs in human cancers remain largely unknown. Aberrant expression and activation of Nrf2 often correlate with chemoresistance and poor prognosis. Here, we report that FoxO3 directs the basal transcription of Keap1, an adaptor protein that bridges Nrf2 to Cul3 for degradation. FoxO3 depletion resulted in Keap1 down-regulation, thereby activating Nrf2 signaling. We further demonstrated that the inhibition of FoxO3-Keap1 axis accounts for Nrf2 induction and activation induced by constitutively active AKT signaling or tumor necrosis factor α (TNFα) treatment. Unlike previous findings, we showed FoxO3 silencing led to decreased reactive oxygen species (ROS) production, therefore protecting cells from oxidative stress-induced killing in an Nrf2-dependent manner. Importantly, FoxO3 deficiency strongly potentiated tumor formation in nude mice and rendered cholangiocarcinoma (CCA) xenografts resistant to cisplatin-induced cell death via activating Nrf2. Additionally, we found that clinical CCA samples displayed FoxO3-Keap1 down-regulation and Nrf2 hyperactivation, underscoring the essential roles of these proteins in CCA development. Conclusion：Our results unravel a unique mechanism underlying the tumor suppressor function of FoxO3 via constraining Nrf2 signaling. This article is protected by copyright. All rights reserved.

Link: http://onlinelibrary.wiley.com/doi/10.1002/hep.28496/full