The raw data of SAM concentration validated by UPLC-MS/MS

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.

Yes相关蛋白（YAP）的激活可使癌症对化疗及靶向治疗产生耐药性。甲硫氨酸可转化为甲基供体，参与DNA、RNA及蛋白质的甲基化修饰，进而调控细胞进程。然而，目前尚不清楚甲硫氨酸是否通过影响YAP活性来调控耐药性。本研究发现，甲硫氨酸剥夺可显著抑制癌细胞中YAP-TEAD复合物的转录活性。甲硫氨酸可促进PRMT1催化的YAP第124位精氨酸的不对称二甲基化修饰（YAP R124me2a）。模拟YAP甲基化可消除甲硫氨酸限制饮食对YAP诱导耐药性的抑制作用。YAP可激活甲硫氨酸转运体SLC43A2的转录，从而增加癌细胞对甲硫氨酸的摄取。敲低SLC43A2可降低YAP R124me2a的水平。SLC43A2抑制剂BCH可增强肿瘤对化疗药物的敏感性。因此，本研究揭示了YAP R124甲基化与SLC43A2之间存在正反馈环路，该环路可促进癌症的耐药性。干扰这一正反馈环路有望成为癌症治疗的潜在策略。