Targeting SLC3A2 Subunit of System XC- is Essential for m6A Reader YTHDC2 to be an Endogenous Ferroptosis Inducer in Lung Adenocarcinoma

The m6A reader YT521-B homology containing 2 (YTHDC2) has been identified to inhibit lung adenocarcinoma (LUAD) tumorigenesis by suppressing solute carrier 7A11 (SLC7A11)-dependent antioxidant function. SLC7A11 is a major functional subunit of system XC-. Inhibition of system XC- can induce ferroptosis. However, whether suppressing SLC7A11 is sufficient for YTHDC2 to be an endogenous ferroptosis inducer in LUAD is unknown. Here, we found that induction of YTHDC2 to a high level can induce ferroptosis in LUAD cells but not in lung and bronchus epithelial cells. In addition to SLC7A11, solute carrier 3A2 (SLC3A2), another subunit of system XC- was equally important for YTHDC2-induced ferroptosis. YTHDC2 m6A-dependently destabilized Homeo box A13 (HOXA13) mRNA because a potential m6A recognition site was identified within its 3' untranslated region (3'UTR). Interestingly, HOXA13 acted as a transcription factor to stimulate SLC3A2 expression. Thereby, YTHDC2 suppressed SLC3A2 via inhibiting HOXA13 in an m6A-indirect manner. Mouse experiments further confirmed the associations among YTHDC2, SLC3A2 and HOXA13, and demonstrated that SLC3A2 and SLC7A11 were both important for YTHDC2-impaired tumor growth and -induced lipid peroxidation in vivo. Moreover, higher expression of SLC7A11, SLC3A2 and HOXA13 indicate poorer clinical outcome in YTHDC2-suppressed LUAD patients. In conclusion, YTHDC2 is believed to be a powerful endogenous ferroptosis inducer and targeting SLC3A2 subunit of system XC- is essential for this process. Increasing YTHDC2 is an alternative ferroptosis-based therapy to treat LUAD.