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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
EF24 targets METTL3 to reprogram m6A methylation and induce ferroptosis: an epitranscriptomic mechanism with
Yang Yang1, Zhou Jianxu1, Liu Hao2
1TCM Department, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China.
Abstract:
Glioma, the most common primary malignant tumor of the central nervous system, still brings a dismal prognosis, even after stringent standard therapies. This study investigates the RNA epitranscriptomic regulatory mechanism of curcumin analog EF24 in inducing ferroptosis to counter glioma. Both in vitro and in vivo experiments demonstrated that EF24 induces significant ferroptosis and effectively suppresses the growth and metastasis of glioma. Mechanistically, EF24 specifically downregulates the m6A methyltransferase METTL3, a core component of the RNA methylation machinery. More specific, METTL3 recruits an m6A reader YTHDF1 to catalyze methylation at the 3'-UTR region of NRF2 mRNA, forming an m6A-YTHDF1-NRF2 translational enhancement complex that activates downstream antioxidant gene GPX4 expression. EF24 disrupts this complex through suppressing NRF2 mRNA stability and impairing its protein translation, ultimately depleting GPX4 and triggering ferroptosis cascades. For the first time, our study proposes an epitranscriptomic axis of METTL3/YTHDF1/NRF2/GPX4 as a regulator of ferroptosis in glioma, which may be targeted to design an effective and safe therapeutic strategy.
Insights
Curcumin analog EF24 triggers ferroptosis in glioma by downregulating METTL3, disrupting the m6A-YTHDF1-NRF2 complex, and depleting GPX4. This novel epitranscriptomic pathway offers a potential therapeutic target for brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Glioma, a primary brain tumor, has a poor prognosis despite standard treatments.
- RNA epitranscriptomics, particularly N6-methyladenosine (m6A) modification, plays a role in cancer progression.
- Ferroptosis, a regulated form of cell death, is a promising therapeutic target in oncology.
Purpose of the Study:
- To investigate the RNA epitranscriptomic regulatory mechanism of curcumin analog EF24 in inducing ferroptosis against glioma.
- To elucidate the role of the m6A methyltransferase METTL3 and its downstream effectors in EF24-mediated glioma suppression.
Main Methods:
- In vitro and in vivo glioma models were utilized.
- The study analyzed the effect of EF24 on cell growth, metastasis, ferroptosis markers, and gene/protein expression.
- RNA immunoprecipitation followed by sequencing (RIP-seq) and Western blotting were employed to confirm molecular interactions.
Main Results:
- EF24 significantly induced ferroptosis and suppressed glioma growth and metastasis.
- EF24 downregulated METTL3, which is crucial for the m6A-YTHDF1-NRF2 complex formation.
- The EF24-induced disruption of this complex led to decreased NRF2 translation and GPX4 expression, triggering ferroptosis.
Conclusions:
- A novel epitranscriptomic axis (METTL3/YTHDF1/NRF2/GPX4) regulating ferroptosis in glioma was identified.
- EF24's mechanism involves targeting this axis to induce cancer cell death.
- This pathway presents a potential therapeutic strategy for glioma treatment.
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