PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma
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...
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Wiley
2025-03-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70272 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zeyu Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0701ed4710184cf9aaca4f2dc69f2dc4 |
| institution | OA Journals |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-0701ed4710184cf9aaca4f2dc69f2dc42025-08-20T02:32:12ZengWileyClinical and Translational Medicine2001-13262025-03-01153n/an/a10.1002/ctm2.70272PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinomaZeyu Wang0Hao Wu1Zhaoxing Li2Zhukai Chen3Anqi Feng4Yuan Chu5Kang Fang6Zehua Zhang7Ziying Zhao8Zhuyun Leng9Shihan Zhang10Xiaoyuan Wang11Lingnan He12Tao Chen13Meidong Xu14Department of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaDepartment of Gastroenterology Endoscopy Center Shanghai East Hospital School of Medicine Tongji University Shanghai ChinaAbstract 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.https://doi.org/10.1002/ctm2.70272cisplatincitrullinationOSCCPADI4PRMT2 |
| spellingShingle | 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 PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma Clinical and Translational Medicine cisplatin citrullination OSCC PADI4 PRMT2 |
| title | PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma |
| title_full | PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma |
| title_fullStr | PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma |
| title_full_unstemmed | PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma |
| title_short | PADI4 facilitates stem‐like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma |
| title_sort | padi4 facilitates stem like properties and cisplatin resistance through upregulating prmt2 ids family in oesophageal squamous cell carcinoma |
| topic | cisplatin citrullination OSCC PADI4 PRMT2 |
| url | https://doi.org/10.1002/ctm2.70272 |
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