GINS4 suppresses ferroptosis by antagonizing p53 acetylation with Snail

Ling Chen; Qidong Cai; Rui Yang; Haiyan Wang; Huli Ling; Tiansheng Li; Na Liu; Zuli Wang; Jingyue Sun; Tania Tao; Ying Shi; Ya Cao; Xiang Wang; Desheng Xiao; Shuang Liu; Yongguang Tao

doi:10.1073/pnas.2219585120

GINS4 suppresses ferroptosis by antagonizing p53 acetylation with Snail

Proc Natl Acad Sci U S A. 2023 Apr 11;120(15):e2219585120. doi: 10.1073/pnas.2219585120. Epub 2023 Apr 5.

Authors

Ling Chen^{1

2

3}, Qidong Cai⁴, Rui Yang^{1

2

5}, Haiyan Wang^{1

2

5}, Huli Ling^{1

2

5}, Tiansheng Li^{1

2

5}, Na Liu^{6

7}, Zuli Wang^{1

2

5}, Jingyue Sun^{1

2

5}, Tania Tao³, Ying Shi^{1

2

3}, Ya Cao^{1

2

3}, Xiang Wang⁴, Desheng Xiao^{2

5}, Shuang Liu⁸, Yongguang Tao^{1

2

3

4

5}

Affiliations

¹ Hunan 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.
² Department of Pathology, Xiangya Hospital, Central South University, Changsha Hunan 410008, China.
³ Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Health Commission Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha Hunan 410078, China.
⁴ Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, Changsha Hunan 410011, China.
⁵ Department of Pathology, School of Basic Medicine, Central South University, Changsha Hunan 410013, China.
⁶ Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha Hunan 410008, China.
⁷ Postdoctoral Research Workstation, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha Hunan 410008, China.
⁸ Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha Hunan 410008, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Cell Cycle
Chromosomal Proteins, Non-Histone / metabolism
Ferroptosis*
Humans
Oxidation-Reduction
Snail Family Transcription Factors / metabolism
Tumor Suppressor Protein p53 / metabolism

Substances

Chromosomal Proteins, Non-Histone
GINS4 protein, human
Tumor Suppressor Protein p53
Snail Family Transcription Factors