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Updated: May 24, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer
Yizeng Fan1,2,3, Yuzhao Wang1,2,3, Weichao Dan1,2,3
1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Abstract:
The activation of ferroptosis has shown great potential for cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into S-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of glutathione peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving cancer therapy efficacy, by acting to reduce the counteraction of ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability.
Insights
Methionine metabolism stabilizes glutathione peroxidase 4 (GPX4) via PRMT5 methylation, preventing its degradation. Inhibiting PRMT5 enhances ferroptosis sensitivity, offering a novel cancer therapy strategy.
Area of Science:
- Biochemistry
- Cancer Biology
- Molecular Oncology
Background:
- Ferroptosis, a regulated cell death, presents a promising cancer therapy avenue.
- Understanding mechanisms suppressing tumor-intrinsic ferroptosis is crucial for effective cancer treatment.
Purpose of the Study:
- To elucidate the role of methionine metabolism in ferroptosis suppression.
- To identify novel therapeutic targets for enhancing ferroptosis-based cancer therapy.
Main Methods:
- Investigated methionine metabolism and its link to glutathione peroxidase 4 (GPX4) stability.
- Utilized protein arginine methyltransferase 5 (PRMT5) inhibition as a therapeutic strategy.
- Assessed ferroptosis induction and tumor progression in vitro and in vivo mouse models.
Main Results:
- Methionine metabolism produces S-adenosylmethionine, methylating GPX4 at R152 via PRMT5, prolonging its half-life.
- PRMT5 inhibition reduces GPX4 levels by impeding methylation and increasing ferroptosis sensitivity.
- GPX4 methylation by PRMT5 prevents FBW7 E3 ligase binding, inhibiting GPX4 degradation.
- Combined PRMT5 inhibition and ferroptosis therapy significantly suppressed tumor growth in mice.
- Elevated GPX4 and decreased FBW7 levels correlate with poor prognosis in human cancers.
Conclusions:
- PRMT5-mediated GPX4 methylation stabilizes GPX4, counteracting ferroptosis in tumors.
- Targeting PRMT5 offers a strategy to enhance ferroptosis-inducing cancer therapies.
- PRMT5 inhibition represents a promising therapeutic approach to overcome tumor resistance to ferroptosis.
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