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Updated: Aug 4, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
GINS4 suppresses ferroptosis by antagonizing p53 acetylation with Snail
Ling Chen1,2,3, Qidong Cai4, Rui Yang1,2,5
1Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha Hunan 410031, China.
Abstract:
Ferroptosis is an iron-dependent oxidative, nonapoptotic form of regulated cell death caused by the destruction of redox homeostasis. Recent studies have uncovered complex cellular networks that regulate ferroptosis. GINS4 is a promoter of eukaryotic G1/S-cell cycle as a regulator of initiation and elongation of DNA replication, but little is known about its impact on ferroptosis. Here, we found that GINS4 was involved in the regulation of ferroptosis in lung adenocarcinoma (LUAD). CRISPR/Cas9-mediated GINS4 KO facilitated ferroptosis. Interestingly, depletion of GINS4 could effectively induce G1, G1/S, S, and G2/M cells to ferroptosis, especially for G2/M cells. Mechanistically, GINS4 suppressed p53 stability through activating Snail that antagonized the acetylation of p53, and p53 lysine residue 351 (K351 for human p53) was the key site for GINS4-suppressed p53-mediated ferroptosis. Together, our data demonstrate that GINS4 is a potential oncogene in LUAD that functions to destabilize p53 and then inhibits ferroptosis, providing a potential therapeutic target for LUAD.
Insights
GINS4 destabilizes p53, inhibiting ferroptosis in lung adenocarcinoma (LUAD). Depleting GINS4 induces cell death, particularly in G2/M cells, offering a potential therapeutic target for LUAD.
Area of Science:
- Cell Biology
- Oncology
- Biochemistry
Background:
- Ferroptosis is regulated cell death crucial for redox homeostasis.
- GINS4 promotes DNA replication but its role in ferroptosis is unclear.
- Lung adenocarcinoma (LUAD) is a major cancer with complex regulatory networks.
Purpose of the Study:
- To investigate the role of GINS4 in ferroptosis regulation in LUAD.
- To elucidate the molecular mechanism by which GINS4 affects ferroptosis.
- To identify GINS4 as a potential therapeutic target in LUAD.
Main Methods:
- CRISPR/Cas9-mediated gene knockout (KO) of GINS4.
- Cell cycle analysis (G1, G1/S, S, G2/M) and ferroptosis induction.
- Western blotting to assess protein stability and acetylation.
- Mechanistic studies involving p53, Snail, and acetylation sites.
Main Results:
- GINS4 knockout (KO) facilitated ferroptosis in LUAD cells.
- GINS4 depletion induced ferroptosis across all cell cycle phases, notably in G2/M cells.
- GINS4 suppressed p53 stability by activating Snail, which inhibited p53 acetylation at K351.
- p53 K351 was identified as critical for GINS4-mediated ferroptosis inhibition.
Conclusions:
- GINS4 acts as an oncogene in LUAD by destabilizing p53 and inhibiting ferroptosis.
- Targeting GINS4 may represent a novel therapeutic strategy for LUAD treatment.
- Understanding the GINS4-p53-ferroptosis axis provides insights into LUAD pathogenesis.
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