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