Epigenetically silenced lncRNA SNAI3-AS1 promotes ferroptosis in glioma via perturbing the m6A-dependent recognition of Nrf2 mRNA mediated by SND1

Background: Ferroptosis has been linked to tumor progression and resistance to antineoplastic therapy. Long noncoding RNA (lncRNA) exerts a regulatory role in various biological processes of tumor cells, while the function and molecular mechanism of lncRNA in Ferroptosis are yet to be clarified in glioma.

Methods: Both gain-of-function and loss-of-function experiments were employed to investigate the effects of SNAI3-AS1 on the tumorigenesis and Ferroptosis susceptibility of glioma in vitro and in vivo. Bioinformatics analysis, Bisulfite Sequencing PCR, RNA pull-down, RIP, MeRIP and dual-luciferase reporter assay were performed to explore the low expression mechanism of SNAI3-AS1 and the downstream mechanism of SNAI3-AS1 in Ferroptosis susceptibility of glioma.

Results: We found that Ferroptosis inducer erastin downregulates SNAI3-AS1 expression in glioma by increasing the DNA methylation level of SNAI3-AS1 promoter. SNAI3-AS1 functions as a tumor suppressor in glioma. Importantly, SNAI3-AS1 enhances the anti-tumor activity of erastin by promoting Ferroptosis both in vitro and in vivo. Mechanistically, SNAI3-AS1 competitively binds to SND1 and perturbs the m⁶A-dependent recognition of Nrf2 mRNA 3'UTR by SND1, thereby reducing the mRNA stability of Nrf2. Rescue experiments confirmed that SND1 overexpression and silence can rescue the gain- and loss-of-function ferroptotic phenotypes of SNAI3-AS1, respectively.

Conclusions: Our findings elucidate the effect and detailed mechanism of SNAI3-AS1/SND1/Nrf2 signalling axis in Ferroptosis, and provide a theoretical support for inducing Ferroptosis to improve glioma treatment.

Ferroptosis; Glioma; LncRNA; Nrf2; m6A.