PRMT5-mediated arginine methylation of HSP90AA1 drives esophageal squamous cell carcinoma progression

Dysregulated HSP90AA1 chaperone activity is a hallmark of multiple cancers; however, its post-translational regulation in esophageal squamous cell carcinoma (ESCC) remains poorly defined. Here, we defined PRMT5-dependent symmetric dimethylation of HSP90AA1 at arginine 182 (R182) as a critical molecular switch driving ESCC progression. HSP90AA1 physically interacted with PRMT5, and genetic or pharmacological inhibition of PRMT5 markedly reduced HSP90AA1 R182 methylation, accompanied by suppression of epithelial-mesenchymal transition (EMT) programs. HSP90AA1 depletion significantly impaired ESCC cell proliferation, migration, and invasion, inducing cell-cycle arrest and EMT reversal. In rescue experiments, re-expression of wild-type HSP90AA1 restored malignant phenotypes both in vitro and in vivo, whereas the methylation-deficient R182A mutant failed to do so. Mechanistically, R182 methylation stabilized key EMT transcription factors, thereby establishing a methylation-chaperone-EMT regulatory axis. Clinically, HSP90AA1 was markedly overexpressed in ESCC tissues and correlated with poor patient outcomes. Therapeutically, dual targeting of PRMT5 and HSP90AA1 exerted potent antitumor effects, suppressing clonogenicity and invasion in vitro and significantly reducing tumor burden in both cell-derived and patient-derived xenograft models. Collectively, these findings established the PRMT5-HSP90AA1 R182 methylation axis as a targetable vulnerability in ESCC and provided a strong rationale for biomarker-driven combinatorial therapeutic strategies.