PSMC2 upregulation enhances epithelial-to-mesenchymal transition in glioblastoma via activating AKT/GSK3β/β-catenin axis.

Glioblastoma multiforme (GBM), a grade IV brain tumor, remains one of the most aggressive and difficult-to-treat cancers, emphasizing the urgent need for novel therapeutic targets. The dysregulation of the unfolded protein response, particularly involving the proteasomal pathway, contributes significantly to the pathogenesis of GBM. Proteasome 26S subunit ATPase 2 (PSMC2) has recently been identified as a potential factor in carcinogenesis; however, the molecular mechanisms involved remain unclear. In this study, we found significantly high expression of PSMC2 in GBM, with increased levels associated with an unfavorable prognosis. PSMC2 knockdown in GBM cell lines reduced proliferation, impaired migration, and induced apoptosis, while its overexpression enhanced epithelial-to-mesenchymal transition (EMT) related marker expression. Further, the tumorigenic effect of PSMC2 was confirmed in vivo as PSMC2 knockdown reduced the tumor volume and weight. Mechanistically, PSMC2 promoted malignancy via nuclear localizing of β-catenin by activating AKT/GSK3β/β-catenin axis, with AKT-mediated inhibitory phosphorylation of GSK3β enabling β-catenin activation. Besides, we used Lithium chloride to induce GSK3β phosphorylation which reversed the effects of PSMC2 knockdown, further validating this pathway. These findings demonstrate that PSMC2 drives GBM progression by regulating the AKT/GSK3β/β-catenin axis, positioning it as a promising biomarker and therapeutic target for GBM.