The hyperactivation of the transcriptional coactivator YAP, a downstream effector of the Hippo pathway, has been implicated in the initiation and progression of human cancers including glioblastoma (GBM), but the underlying mechanisms remain elusive. In this study, we demonstrate that methionine promotes YAP activation through PRMT5-mediated symmetrical dimethylation (sDMA) at a conserved arginine residue within five conserved LATS-targeting motifs (HXRXXS), with R124 identified as the primary site of modification. R124 sDMA (R124me2s) serves as a physiological protective mechanism against LATS-mediated inhibitory phosphorylation of YAP at Ser127, thereby facilitating YAP nuclear translocation and enhancing its transcriptional activity. Moreover, YAP R124 sDMA drives tumor methionine addiction and tumorigenicity of GBM through a feedforward loop in which YAP transcriptionally upregulates PRMT5 and the methionine transporters SLC3A2/SLC7A5. Furthermore, radiation activates PRMT5-YAP-SLC3A2/7A5 axis to promote GBM cell survival. Inhibiting this signaling axis in combination with radiotherapy impairs intracranial xenograft growth, resulting in significant survival extensions for treated animals. Overall, our findings uncover a previously unrecognized regulatory axis where PRMT5-mediated R124me2s governs YAP activation through a feedback mechanism, presenting novel therapeutic vulnerabilities in GBM.
Keywords: GBM; PRMT5; Radioresistance; SLC3A2; SLC7A5; YAP.
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