甲基化
癌症研究
GPX4
顺铂
蛋白质精氨酸甲基转移酶5
甲基转移酶
化学
脂质过氧化
生物
谷胱甘肽
生物化学
酶
谷胱甘肽过氧化物酶
基因
化疗
遗传学
作者
Yiru Wang,Can Wang,Xiaojiao Guan,Yihui Ma,Shijie Zhang,Fēi Li,Yuyao Yin,Zhenxing Sun,Xiuwei Chen,Hang Yin
标识
DOI:10.1002/advs.202303812
摘要
Abstract Protein arginine methyltransferase (PRMT) plays essential roles in tumor initiation and progression, but its underlying mechanisms in the treatment sensitivity of endometrial cancer (EC) remain unclear and warrant further investigation. Here, a comprehensive analysis of the Cancer Genome Atlas database and Clinical Proteomic Tumor Analysis Consortium database identifies that PRMT3 plays an important role in EC. Specifically, further experiments show that PRMT3 inhibition enhances the susceptibility of EC cells to ferroptosis. Mechanistically, PRMT3 interacts with Methyltransferase 14 (METTL14) and is involved in its arginine methylation. In addition, PRMT3 inhibition‐mediated METTL14 overexpression promotes methylation modification via an m 6 A‐YTHDF2‐dependent mechanism, reducing Glutathione peroxidase 4 (GPX4) mRNA stability, increasing lipid peroxidation levels, and accelerating ferroptosis. Notably, combined PRMT3 blockade and anti‐PD‐1 therapy display more potent antitumor effects by accelerating ferroptosis in cell‐derived xenograft models. The specific PRMT3 inhibitor SGC707 exerts the same immunotherapeutic sensitizing effect in a patient‐derived xenograft model. Notably, blocking PRMT3 improves tumor suppression in response to cisplatin and radiation therapy. Altogether, this work demonstrates that PRMT3 depletion is a promising target for EC.
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