FOXO1/miR-506/ETS1 feedback loop promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma

Purpose Glioblastoma multiforme (GBM) is the most lethal brain tumor which is characterized of high invasiveness and resistance to chemoradiotherapy. Forkhead box protein O1 (FOXO1) might play a key role in multidrug resistance (MDR) and invasiveness of GBM, while the upstream and downstream molecular mechanisms are not yet elucidated. Methods The roles of FOXO1 and miR-506 in proliferation, apoptosis, migration, invasion, autophagy and TMZ sensitivity were explored in U251 cell lines both in vitro and in vivo . The interaction between FOXO1and miR-506 was also explored. Results In this study, we found FOXO1/ miR-506 axis suppresses GBM cells invasion and migration, and promotes chemosensitivity to temozolomide (TMZ) which was mediated by autophagy. FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation. miR-506 could down-regulate ETS1 expression by targeting its 3’-UTR. Interestingly, ETS1 promotes FOXO1 translocation from nucleus to cytosol and further suppresses FOXO1-miR-506 axis in GBM cells. Consistently, both miR-506 inhibition and ETS1 overexpression can rescue FOXO1 overactivation mediated TMZ chemosensitivity in mouse models. Conclusions These results demonstrate a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM to regulate invasiveness and chemosensitivity, which might be a promising therapeutic target for GBM.