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Targeting SLC3A2 subunit of system XC- is essential for m6A reader YTHDC2 to be an endogenous ferroptosis inducer in
Lifang Ma1, Xiao Zhang2, Keke Yu3
1Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
Abstract:
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.
Insights
YTHDC2 induces ferroptosis in lung adenocarcinoma by regulating SLC3A2 and SLC7A11. This involves destabilizing HOXA13 mRNA, highlighting YTHDC2 as a potential therapeutic target for LUAD.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- YTHDC2 (YT521-B homology containing 2) inhibits lung adenocarcinoma (LUAD) by suppressing SLC7A11-dependent antioxidant function.
- System XC-, comprising SLC7A11, is crucial for cellular antioxidant defense and its inhibition can trigger ferroptosis.
Purpose of the Study:
- To investigate if YTHDC2 can act as an endogenous ferroptosis inducer in LUAD by targeting system XC-.
- To elucidate the molecular mechanisms underlying YTHDC2-mediated ferroptosis in LUAD.
Main Methods:
- Cell culture experiments to assess ferroptosis induction by YTHDC2 in LUAD and normal lung cells.
- mRNA stability assays and Western blotting to analyze the impact of YTHDC2 on HOXA13, SLC3A2, and SLC7A11.
- In vivo mouse models to validate findings and assess tumor growth and lipid peroxidation.
- Analysis of clinical data to correlate gene expression with patient outcomes.
Main Results:
- High YTHDC2 levels induced ferroptosis in LUAD cells but not in normal lung epithelial cells.
- Both SLC7A11 and SLC3A2 subunits of system XC- were essential for YTHDC2-induced ferroptosis.
- YTHDC2 destabilized HOXA13 mRNA in an m6A-dependent manner, indirectly suppressing SLC3A2 expression.
- Mouse studies confirmed YTHDC2, SLC3A2, and HOXA13 interactions, with SLC3A2 and SLC7A11 impacting tumor growth and lipid peroxidation.
- Elevated SLC7A11, SLC3A2, and HOXA13 expression correlated with poorer outcomes in LUAD patients with suppressed YTHDC2.
Conclusions:
- YTHDC2 functions as a potent endogenous ferroptosis inducer in LUAD.
- Targeting the SLC3A2 subunit of system XC- is critical for YTHDC2-mediated ferroptosis.
- Increasing YTHDC2 expression represents a potential ferroptosis-based therapeutic strategy for LUAD.
