PADI4 facilitates stem-like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2025-03-13 DOI:10.1002/ctm2.70272

Zeyu Wang, Hao Wu, Zhaoxing Li, Zhukai Chen, Anqi Feng, Yuan Chu, Kang Fang, Zehua Zhang, Ziying Zhao, Zhuyun Leng, Shihan Zhang, Xiaoyuan Wang, Lingnan He, Tao Chen, Meidong Xu

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Abstract

Background

Oesophageal squamous cell carcinoma (OSCC) is a highly lethal cancer characterized by its aggressive nature and chemotherapy resistance. Peptidylarginine deiminase 4 (PADI4) regulates protein citrullination and is associated with various cancer developments. The role of PADI4 in OSCC progression and chemoresistance remains unexplored.

Methods

The protein interactions were conducted by immunoprecipitation assays. Quantitative real-time PCR and western blotting were utilized to quantifyexpression levels in cancer cells. The stem-like properties were assessed through spheroid growth assays and Cancer Stem Cells (CSCs) markers. Additionally, the resistance of cancer cells to cisplatin was evaluated using CCK8 assay.

Results

This study shows that PADI4 promotes cellular stemness, contributing to the progression and chemoresistance of OSCC. Mechanistically, PADI4 facilitates the citrullination of protein arginine methyltransferase 2 (PRMT2), a process essential for the stabilization of PRMT2 expression and the enhancement of its function in promoting the transcription of IDs family (ID1 and ID2) via histone arginine methylation. This mechanism subsequently increases tumour stemness and contributes to the cisplatin resistance observed in OSCC. Mutations at the R312 site or inhibition by GSK484 can attenuate tumour stemness in OSCC, thereby reducing cisplatin resistance.

Conclusion

PADI4 promotes citrullination and stabilization of PRMT2, enhancing its function in upregulating ID1 and ID2 expression via histone arginine methylation, which increases stemness and contributes to cisplatin resistance in OSCC; this effect can be mitigated by R312 mutations or GSK484 inhibition, reducing stemness and cisplatin resistance.

Key points

The role of citrullinization in cisplatin resistance of OSCC.
PADI4 citrullinate of PRMT2 and stabilize PRMT2.
PADI4 citrullinate of PRMT2 promoting the transcription of IDs family (ID1, ID2 and ID3) via histone arginine methylation.
PADI4 citrullinated PRMT2 affected the combination of PRMT2 and USP7.
PADI4 citrullinate of PRMT2 at R312 site.
PADI4 inhibitor GSK484 can affect the stemness of OSCC and cisplatin resistance.

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.