PRMT5-Mediated Arginine Methylation of HSP90AA1 Drives Esophageal Squamous Cell Carcinoma Progression

Abstract

Dysregulated HSP90AA1 chaperone activity is a hallmark of multiple human cancers, yet its post-translational modifications in esophageal squamous cell carcinoma (ESCC) are poorly defined. Here, we identify a PRMT5-driven modification of HSP90AA1, symmetric dimethylation at arginine 182 (R182), as a pivotal switch that fuels ESCC progression. HSP90AA1 physically associates with PRMT5, and genetic or pharmacologic PRMT5 blockade diminishes HSP90AA1-R182 methylation and downstream oncogenic signaling. Functionally, HSP90AA1 loss suppresses ESCC cell proliferation, migration, and invasion; enforces cell cycle arrest and reverses epithelial-mesenchymal transition (EMT). Re-expression of wild-type HSP90AA1 rescues cancer cell growth and EMT in vitro and in vivo, whereas the methylation-deficient R182A mutant does not. Furthermore, clinically oriented analysis shows HSP90AA1 overexpression in ESCC tissues and indicates moderate prognostic utility. Moreover, dual targeting of the PRMT5/HSP90AA1 axis is therapeutically attractive, and combined PRMT5/HSP90AA1 inhibition acts synergistically to exert anti-tumor activity, markedly reducing clonogenicity, invasion, and tumor burden in both cell-derived and patient-derived xenograft models. These findings demonstrate that PRMT5/HSP90AA1 serve as mechanistic drivers and actionable biomarkers in ESCC and provide a rationale for biomarker-guided co-inhibition of PRMT5/HSP90AA1 in translational studies.