Positive Feedback Between Arginine Methylation of YAP and Methionine Transporter SLC43A2 Drives Anticancer Drug Resistance

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Jan 3

PMID 39747898

Authors

Xia-Lu Hong

Chen-Kai Huang

Hui Qian

Chen-Hong Ding

Fang Liu

Huan-Yu Hong

Shu-Qing Liu

Si-Han Wu

Xin Zhang

Wei-Fen Xie

Affiliations

Soon will be listed here.

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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