Oncogenic Forkhead box D3 antisense RNA 1 promotes cell survival and confers temozolomide resistance in glioblastoma cells through the miR-128-3p/WEE1 G2 checkpoint kinase axis

Abstract

ABSTRACT Although temozolomide (TMZ) is recommended for glioblastoma (GBM) treatment, patients treated with TMZ usually develop TMZ resistance. Thus, there is an urgent need to elucidate the mechanism through which GBM cells acquire TMZ resistance. FOXD3-AS1, a recently discovered lncRNA, shows high expression in diverse cancer types. Nonetheless, its role in GBM remains unclear. This study found that FOXD3-AS1 was overexpressed in GBM cells and associated with dismal prognostic outcome in GBM patients. Functional studies revealed that depletion of FOXD3-AS1 inhibited cell growth and induced apoptosis of GBM cells. Results also showed that FOXD3-AS1 participates in the tolerance of GBM cells to TMZ. Specifically, TMZ-resistant cells exhibited higher FOXD3-AS1 expression compared to parental cells. Overexpression of FOXD3-AS1 increased TMZ tolerance in TMZ sensitive cells, whereas depletion of FOXD3-AS1 sensitized TMZ-resistant cells to TMZ treatment. Mechanistically, WEE1 was positively expressed with FOXD3-AS1. Given that both FOXD3-AS1 and WEE1 contain a binding site for miR-128-3p, FOXD3-AS1 could act as a competing endogenous RNA (ceRNA) to promote WEE1 expression by sponging miR-128-3p. Furthermore, we demonstrated that WEE1 was upregulated in TMZ-resistant GBM cells. Overexpression of WEE1 increased TMZ tolerance in TMZ sensitive cells, whereas deletion of FOXD3-AS1 promoted TMZ-resistant cells to be more sensitive to TMZ. Importantly, depletion of WEE1 could reverse TMZ resistant phenotype in FOXD3-AS1-overexpressed GBM cells. Collectively, our findings reveal a critical role of FOXD3-AS1 in the survival of GBM cells and TMZ resistance, which suggests that FOXD3-AS1 is a potential biomarker for the diagnosis and treatment of GBM.