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.