YTHDF2 promotes temozolomide resistance in glioblastoma by activation of the Akt and NF‐κB signalling pathways via inhibiting EPHB3 and TNFAIP3

Abstract Objectives Temozolomide (TMZ) resistance is a key factor that restricts the therapeutic effect of glioblastoma (GBM). YTH‐domain family member 2 (YTHDF2) is highly expressed in GBM tissues, while the mechanism of YTHDF2 in TMZ resistance in GBM remains not fully elucidated. Methods The YTHDF2 expression in TMZ‐resistant tissues and cells was detected. Kaplan–Meier analysis was employed to evaluate the prognostic value of YTHDF2 in GBM. Effect of YTHDF2 in TMZ resistance in GBM was explored via corresponding experiments. RNA sequence, FISH in conjugation with fluorescent immunostaining, RNA immunoprecipitation, dual‐luciferase reporter gene and immunofluorescence were applied to investigate the mechanism of YTHDF2 that boosted TMZ resistance in GBM. Results YTHDF2 was up‐regulated in TMZ‐resistant tissues and cells, and patients with high expression of YTHDF2 showed lower survival rate than the patients with low expression of YTHDF2. The elevated YTHDF2 expression boosted TMZ resistance in GBM cells, and the decreased YTHDF2 expression enhanced TMZ sensitivity in TMZ‐resistant GBM cells. Mechanically, YTHDF2 bound to the N6‐methyladenosine (m6A) sites in the 3′UTR of EPHB3 and TNFAIP3 to decrease the mRNA stability. YTHDF2 activated the PI3K/Akt and NF‐κB signals through inhibiting expression of EPHB3 and TNFAIP3, and the inhibition of the two pathways attenuated YTHDF2‐mediated TMZ resistance. Conclusion YTHDF2 enhanced TMZ resistance in GBM by activation of the PI3K/Akt and NF‐κB signalling pathways via inhibition of EPHB3 and TNFAIP3.