在食管鳞状细胞癌中，PADI4通过上调PRMT2/IDs家族促进干细胞样特性和顺铂耐药性。

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

作者信息

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

机构信息

Department of Gastroenterology, Endoscopy Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.

出版信息

Clin Transl Med. 2025 Mar;15(3):e70272. doi: 10.1002/ctm2.70272.

DOI:10.1002/ctm2.70272

PMID:40078091

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11904308/

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.

摘要

背景

食管鳞状细胞癌（OSCC）是一种具有高度致死性的癌症，具有侵袭性和化疗耐药性。肽基精氨酸脱亚氨酶4（PADI4）调节蛋白质瓜氨酸化，并与多种癌症的发展相关。PADI4在OSCC进展和化疗耐药中的作用尚待探索。

方法

通过免疫沉淀试验进行蛋白质相互作用研究。利用定量实时PCR和蛋白质印迹法来定量癌细胞中的表达水平。通过球体生长试验和癌症干细胞（CSC）标志物评估干细胞样特性。此外，使用CCK8试验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，导致OSCC的进展和化疗耐药。机制上，PADI4促进蛋白质精氨酸甲基转移酶2（PRMT2）的瓜氨酸化，这一过程对于稳定PRMT2表达以及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。该机制随后增加肿瘤干性，并导致OSCC中观察到的顺铂耐药。R312位点的突变或GSK484的抑制可减弱OSCC中的肿瘤干性，从而降低顺铂耐药性。

结论

PADI4促进PRMT2的瓜氨酸化和稳定，增强其通过组蛋白精氨酸甲基化上调ID1和ID2表达的功能，从而增加干性并导致OSCC中的顺铂耐药；R312突变或GSK484抑制可减轻这种效应，降低干性和顺铂耐药性。

关键点

瓜氨酸化在OSCC顺铂耐药中的作用。PADI4对PRMT2进行瓜氨酸化并使其稳定。PADI4对PRMT2的瓜氨酸化通过组蛋白精氨酸甲基化促进IDs家族（ID1、ID2和ID3）的转录。PADI4瓜氨酸化的PRMT2影响PRMT2与USP7的结合。PADI4在R312位点对PRMT2进行瓜氨酸化。PADI4抑制剂GSK484可影响OSCC的干性和顺铂耐药性。