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

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

  • Nat Commun. 2025 Jan 2;16(1):87. doi: 10.1038/s41467-024-55769-8.
Xia-Lu Hong # 1,  Chen-Kai Huang # 2,  Hui Qian # 1,  Chen-Hong Ding 3,  Fang Liu 1,  Huan-Yu Hong 1,  Shu-Qing Liu 1,  Si-Han Wu 1,  Xin Zhang 4,  Wei-Fen Xie 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China.
  • 2 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.
  • 3 Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 4 Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China. zhang68@hotmail.com.
  • 5 Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China. weifenxie@medmail.com.cn.
  • # Contributed equally.
PMID: 39747898 DOI: 10.1038/s41467-024-55769-8
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.

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