PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-04-22 Epub Date: 2025-03-28 DOI:10.1016/j.celrep.2025.115484

Qiaoxi Xia, Ronghui Zhong, Jingfang Zheng, Xiao Zhou, Xinwei Zhao, Sisi Wang, Botao Wang, Quanfeng Wu, Chen Xie, Beihua Kong, Qing Zhang, Tianzhi Huang

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Abstract

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.

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prmt5介导的METTL3甲基化通过促进DNA修复机制促进卵巢癌顺铂耐药。

顺铂（CDDP）是一种广泛应用于治疗各种实体肿瘤的化疗药物。然而，对CDDP的耐药性严重阻碍了患者的预后。该研究表明，蛋白精氨酸甲基转移酶（PRMT）5在R36残基上甲基化METTL3 (METTL3- r36me2)，这对卵巢癌（OC）细胞的CDDP耐药至关重要。CDDP暴露后，MST4被核因子-红细胞2相关因子2 （NRF2）反激活，NRF2是抗氧化反应的关键调节因子。MST4刺激PRMT5的甲基转移酶活性，并通过Ser439和Ser463磷酸化促进其与METTL3的相互作用，导致METTL3- r36me2水平升高和腺苷（m6A） N6位置mRNA甲基化。METTL3-R36me2被招募到DNA损伤位点，促进RAD51的招募，进行同源重组（HR）介导的双链断裂修复（DSBR），增强对CDDP的抗性。重要的是，通过抑制PRMT5或METTL3靶向METTL3- r36me2可破坏HR-DSBR并增强CDDP在卵巢肿瘤异种移植物中的细胞毒性作用。因此，我们得出结论，METTL3-R36me2是克服OC中CDDP耐药的可行治疗靶点。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.