PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms
Summary: Cisplatin (CDDP) is a widely used chemotherapy drug for treating various solid tumors. However, resistance to CDDP significantly hampers patient outcomes. This study reveals that protein arginine methyltransferase (PRMT)5 methylates METTL3 at the R36 residue (METTL3-R36me2), which is crucia...
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Elsevier
2025-04-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725002554 |
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| author | Qiaoxi Xia Ronghui Zhong Jingfang Zheng Xiao Zhou Xinwei Zhao Sisi Wang Botao Wang Quanfeng Wu Chen Xie Beihua Kong Qing Zhang Tianzhi Huang |
| author_facet | Qiaoxi Xia Ronghui Zhong Jingfang Zheng Xiao Zhou Xinwei Zhao Sisi Wang Botao Wang Quanfeng Wu Chen Xie Beihua Kong Qing Zhang Tianzhi Huang |
| author_sort | Qiaoxi Xia |
| collection | DOAJ |
| description | Summary: Cisplatin (CDDP) is a widely used chemotherapy drug for treating various solid tumors. However, resistance to CDDP significantly hampers patient outcomes. This study reveals that protein arginine methyltransferase (PRMT)5 methylates METTL3 at the R36 residue (METTL3-R36me2), which is crucial for CDDP resistance in ovarian cancer (OC) cells. Following CDDP exposure, MST4 is transactivated by nuclear factor-erythroid 2-related factor 2 (NRF2), a key regulator of antioxidant responses. MST4 stimulates PRMT5’s methyltransferase activity and promotes its interaction with METTL3 via phosphorylation at Ser439 and Ser463, resulting in increased levels of METTL3-R36me2 and mRNA methylation at the N6 position of adenosine (m6A). The METTL3-R36me2 is recruited to DNA damage sites to promote RAD51 recruitment for homologous recombination (HR)-mediated double-strand break repair (DSBR) and enhance CDDP resistance. Importantly, targeting METTL3-R36me2 through inhibition of PRMT5 or METTL3 disrupts HR-DSBR and augments the cytotoxic effects of CDDP in ovarian tumor xenografts. Therefore, we conclude that METTL3-R36me2 represents a viable therapeutic target for overcoming CDDP resistance in OC. |
| format | Article |
| id | doaj-art-164ad830e8a14dcc928b0e4e19f85b7a |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-164ad830e8a14dcc928b0e4e19f85b7a2025-08-20T02:10:23ZengElsevierCell Reports2211-12472025-04-0144411548410.1016/j.celrep.2025.115484PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanismsQiaoxi Xia0Ronghui Zhong1Jingfang Zheng2Xiao Zhou3Xinwei Zhao4Sisi Wang5Botao Wang6Quanfeng Wu7Chen Xie8Beihua Kong9Qing Zhang10Tianzhi Huang11State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, ChinaState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, ChinaDepartment of Gynecology, Department of Obstetrics and Gynecology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361102, ChinaState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, ChinaState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, ChinaState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, ChinaState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, ChinaDepartment of Obstetrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, ChinaMedical Research Center, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, ChinaDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University; Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, Shandong 250012, ChinaDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University; Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, Shandong 250012, China; Corresponding authorState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518057, China; Corresponding authorSummary: Cisplatin (CDDP) is a widely used chemotherapy drug for treating various solid tumors. However, resistance to CDDP significantly hampers patient outcomes. This study reveals that protein arginine methyltransferase (PRMT)5 methylates METTL3 at the R36 residue (METTL3-R36me2), which is crucial for CDDP resistance in ovarian cancer (OC) cells. Following CDDP exposure, MST4 is transactivated by nuclear factor-erythroid 2-related factor 2 (NRF2), a key regulator of antioxidant responses. MST4 stimulates PRMT5’s methyltransferase activity and promotes its interaction with METTL3 via phosphorylation at Ser439 and Ser463, resulting in increased levels of METTL3-R36me2 and mRNA methylation at the N6 position of adenosine (m6A). The METTL3-R36me2 is recruited to DNA damage sites to promote RAD51 recruitment for homologous recombination (HR)-mediated double-strand break repair (DSBR) and enhance CDDP resistance. Importantly, targeting METTL3-R36me2 through inhibition of PRMT5 or METTL3 disrupts HR-DSBR and augments the cytotoxic effects of CDDP in ovarian tumor xenografts. Therefore, we conclude that METTL3-R36me2 represents a viable therapeutic target for overcoming CDDP resistance in OC.http://www.sciencedirect.com/science/article/pii/S2211124725002554CP: CancerCP: Molecular biology |
| spellingShingle | Qiaoxi Xia Ronghui Zhong Jingfang Zheng Xiao Zhou Xinwei Zhao Sisi Wang Botao Wang Quanfeng Wu Chen Xie Beihua Kong Qing Zhang Tianzhi Huang PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms Cell Reports CP: Cancer CP: Molecular biology |
| title | PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms |
| title_full | PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms |
| title_fullStr | PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms |
| title_full_unstemmed | PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms |
| title_short | PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms |
| title_sort | prmt5 mediated methylation of mettl3 promotes cisplatin resistance in ovarian cancer by facilitating dna repair mechanisms |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725002554 |
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