The N6‐methyladenosine modification enhances ferroptosis resistance through inhibiting SLC7A11 mRNA deadenylation in hepatoblastoma

Abstract

Background Solute carrier family 7 member 11 (SLC7A11) is overexpressed in multiple human tumours and functions as a transporter importing cystine for glutathione biosynthesis. It promotes tumour development in part by suppressing ferroptosis, a newly identified form of cell death that plays a pivotal role in the suppression of tumorigenesis. However, the role and underlying mechanisms of SLC7A11‐mediated ferroptosis in hepatoblastoma (HB) remain largely unknown. Methods Reverse transcription quantitative real‐time PCR (RT‐qPCR) and western blotting were used to measure SLC7A11 levels. Cell proliferation, colony formation, lipid reactive oxygen species (ROS), MDA concentration, 4‐HNE, GSH/GSSG ratio and cell death assays as well as subcutaneous xenograft experiments were used to elucidate the effects of SLC7A11 in HB cell proliferation and ferroptosis. Furthermore, MeRIP‐qPCR, dual luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP) and RACE‐PAT assays were performed to elucidate the underlying mechanism through which SLC7A11 was regulated by the m6A modification in HB. Results SLC7A11 expression was highly upregulated in HB. SLC7A11 upregulation promoted HB cell proliferation in vitro and in vivo, inhibiting HB cell ferroptosis. Mechanistically, SLC7A11 mRNA exhibited abnormal METTL3‐mediated m6A modification, which enhanced its stability and expression. IGF2 mRNA‐binding protein 1 (IGF2BP1) was identified as the m6A reader of SLC7A11, enhancing SLC7A11 mRNA stability and expression by inhibiting SLC7A11 mRNA deadenylation in an m6A‐dependent manner. Moreover, IGF2BP1 was found to block BTG2/CCR4‐NOT complex recruitment via competitively binding to PABPC1, thereby suppressing SLC7A11 mRNA deadenylation. Conclusions Our findings demonstrated that the METTL3‐mediated SLC7A11 m6A modification enhances HB ferroptosis resistance. The METTL3/IGF2BP1/m6A modification promotes SLC7A11 mRNA stability and upregulates its expression by inhibiting the deadenylation process. Our study highlights a critical role of the m6A modification in SLC7A11‐mediated ferroptosis, providing a potential strategy for HB therapy through blockade of the m6A‐SLC7A11 axis.

Frontiers of Ferroptosis in Cancer Treatment

“…IGF2BP1 competitively interacted with PABPC1 and blocked interaction of the CCR4-NOT complexes with PABPC1 (Fig. 2) (111).…”

System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

“…Mechanistic investigation identified SLC7A11 was a direct target of METTL14. Both in vitro and in vivo assay demonstrated that METTL14 induced N6 -methyladenosine (m 6 A) modification at 5′UTR of SLC7A11 mRNA, which promotes SLC7A11 mRNA stability and upregulates its expression by inhibiting the deadenylation process, enhancing ferroptosis resistance ( Fan et al, 2021 ; Liu L. et al, 2022 ; Hill and Liu, 2022 ; Peng and Mo, 2022 ). Additionally, some small molecular inhibitors such as Erastin ( Dixon et al, 2014 ).…”

The Role of SLC7A11 in Cancer: Friend or Foe?

“…The N6-methyladenosine (m6A) modification plays a key role in SLC7A11-mediated ferroptosis. The METTL3-mediated m6A modification promotes SLC7A11 mRNA stability and upregulates its expression [127]. NF-κB-activating protein (NKAP)-an RNA-binding protein to m6A-could promote SLC7A11 mRNA splicing and maturation to suppress ferroptosis in GBM [128].…”