Targeting SLC3A2 subunit of system XC- is essential for m6A reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma.

Lifang Ma, Xiao Zhang, Keke Yu, Xin Xu, Tianxiang Chen, Yi Shi, Yikun Wang, Shiyu Qiu, Susu Guo, Jiangtao Cui, Yayou Miao, Xiaoting Tian, Lutao Du, Yongchun Yu, Jinjing Xia, Jiayi Wang

Free radical biology & medicine 2021 May 20

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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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Lifang Ma, Xiao Zhang, Keke Yu, Xin Xu, Tianxiang Chen, Yi Shi, Yikun Wang, Shiyu Qiu, Susu Guo, Jiangtao Cui, Yayou Miao, Xiaoting Tian, Lutao Du, Yongchun Yu, Jinjing Xia, Jiayi Wang. Targeting SLC3A2 subunit of system XC- is essential for m6A reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma. Free radical biology & medicine. 2021 May 20;168:25-43