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.

Abstract Image

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PADI4在食管鳞状细胞癌中通过上调PRMT2/IDs家族促进茎样特性和顺铂耐药

背景食管鳞状细胞癌（OSCC）是一种具有侵袭性和化疗耐药性的高致死性癌症。肽精氨酸脱亚胺酶4 （PADI4）调节蛋白瓜氨酸化并与多种癌症的发展有关。PADI4在OSCC进展和化疗耐药中的作用尚不清楚。方法采用免疫沉淀法观察蛋白相互作用。采用实时荧光定量PCR和western blotting技术对肿瘤细胞中的表达水平进行定量分析。通过球体生长试验和癌症干细胞（CSCs）标记物评估干细胞样特性。此外，使用CCK8测定法评估癌细胞对顺铂的耐药性。结果本研究表明PADI4促进细胞干性，参与OSCC的进展和化疗耐药。在机制上，PADI4促进了蛋白精氨酸甲基转移酶2 （PRMT2）的瓜氨酸化，这一过程对于稳定PRMT2的表达和增强其通过组蛋白精氨酸甲基化促进IDs家族（ID1和ID2）转录的功能至关重要。这种机制随后增加了肿瘤的干性，并有助于在OSCC中观察到的顺铂耐药性。R312位点突变或GSK484抑制可减弱OSCC的肿瘤干性，从而降低顺铂耐药性。结论PADI4促进PRMT2的瓜氨酸化和稳定化，通过组蛋白精氨酸甲基化增强其上调ID1和ID2表达的功能，从而增加鳞状细胞癌的干性并促进顺铂耐药；这种效应可以通过R312突变或GSK484抑制来减轻，从而降低干细胞的干性和顺铂耐药性。瓜氨酸化在OSCC顺铂耐药中的作用。PADI4瓜氨酸化PRMT2，稳定PRMT2。PRMT2的PADI4瓜氨酸通过组蛋白精氨酸甲基化促进IDs家族（ID1， ID2和ID3）的转录。PADI4瓜氨酸化PRMT2影响PRMT2与USP7的结合。PRMT2在R312位点的PADI4瓜氨酸。PADI4抑制剂GSK484可影响OSCC的干性和顺铂耐药性。

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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.