YAP的精氨酸甲基化与甲硫氨酸转运蛋白SLC43A2之间的正反馈驱动抗癌药物耐药性。

Positive feedback between arginine methylation of YAP and methionine transporter SLC43A2 drives anticancer drug resistance.

作者信息

Hong Xia-Lu, Huang Chen-Kai, Qian Hui, Ding Chen-Hong, Liu Fang, Hong Huan-Yu, Liu Shu-Qing, Wu Si-Han, Zhang Xin, Xie Wei-Fen

机构信息

Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China.

Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.

出版信息

Nat Commun. 2025 Jan 2;16(1):87. doi: 10.1038/s41467-024-55769-8.

DOI:10.1038/s41467-024-55769-8

PMID:39747898

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11697449/

Abstract

Yes-associated protein (YAP) activation confers resistance to chemotherapy and targeted therapy. Methionine participates in cellular processes by converting to methyl donor for the methylation of DNA, RNA and protein. However, it remains unclear whether methionine affects drug resistance by influencing YAP activity. In this study, we report that methionine deprivation remarkably suppresses the transcriptional activity of YAP-TEAD in cancer cells. Methionine promotes PRMT1-catalyzed asymmetric dimethylation at R124 of YAP (YAP R124me2a). Mimicking of YAP methylation abolishes the reduction effect of methionine-restricted diet on YAP-induced drug resistance. YAP activates the transcription of SLC43A2, the methionine transporter, to increase methionine uptake in cancer cells. Knockdown of SLC43A2 decreases the level of YAP R124me2a. BCH, the inhibitor of SLC43A2, sensitizes tumors to anticancer drugs. Thus, our results unravel the positive feedback between YAP R124 methylation and SLC43A2 that contributes to anticancer drug resistance. Disrupting this positive feedback could be a potential strategy for cancer therapy.

摘要

Yes相关蛋白（YAP）的激活赋予了对化疗和靶向治疗的抗性。甲硫氨酸通过转化为DNA、RNA和蛋白质甲基化的甲基供体参与细胞过程。然而，甲硫氨酸是否通过影响YAP活性来影响耐药性仍不清楚。在本研究中，我们报告甲硫氨酸剥夺显著抑制癌细胞中YAP-TEAD的转录活性。甲硫氨酸促进PRMT1催化的YAP第124位精氨酸的不对称二甲基化（YAP R124me2a）。模拟YAP甲基化消除了甲硫氨酸限制饮食对YAP诱导的耐药性的降低作用。YAP激活甲硫氨酸转运体SLC43A2的转录，以增加癌细胞中甲硫氨酸的摄取。敲低SLC43A2可降低YAP R124me2a的水平。SLC43A2的抑制剂BCH使肿瘤对抗癌药物敏感。因此，我们的结果揭示了YAP R124甲基化与SLC43A2之间的正反馈，这有助于抗癌药物耐药性。破坏这种正反馈可能是癌症治疗的一种潜在策略。