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

Xia-Lu Hong, Chen-Kai Huang, Hui Qian, Chen-Hong Ding, Fang Liu, Huan-Yu Hong, Shu-Qing Liu, Si-Han Wu, Xin Zhang () and Wei-Fen Xie ()
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Xia-Lu Hong: Naval Medical University
Chen-Kai Huang: Nanchang University
Hui Qian: Naval Medical University
Chen-Hong Ding: Tongji University
Fang Liu: Naval Medical University
Huan-Yu Hong: Naval Medical University
Shu-Qing Liu: Naval Medical University
Si-Han Wu: Naval Medical University
Xin Zhang: Naval Medical University
Wei-Fen Xie: Naval Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55769-8

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