HSPA5 promotes YAP/TAZ stability independently of the Hippo pathway and induces proneural-to-mesenchymal transition in glioblastoma

The proneural-to-mesenchymal transition (PMT) is a pivotal process in glioblastoma (GBM), driving enhanced tumor aggressiveness, therapeutic resistance, and recurrence. HSPA5, a member of the heat shock protein 70 (HSP70) family, plays a crucial role in regulating and maintaining protein stability and function. Although HSPA5 is a recognized marker of poor prognosis in glioma, its underlying mechanistic function remains poorly defined. Here, we demonstrated that HSPA5 expression is highest in the mesenchymal (MES) subtype of GBM. The overexpression of HSPA5 in proneural (PN) cells induced PMT and promoted malignant phenotypes, whereas its knockdown in MES cells suppressed PMT and attenuated tumorigenicity. We further established that HSPA5 drives PMT by activating the YAP/TAZ pathway in vitro and in vivo. The expression of MES markers CD44 and c-MET was transcriptionally regulated by YAP/TAZ. Mechanistically, HSPA5 interacts directly with YAP/TAZ, disrupting their association with β-TrCP. This protective interaction inhibits the ubiquitination and proteasomal degradation of YAP/TAZ. Furthermore, HSPA5 expression was positively correlated with YAP and TAZ levels across GBM subtypes. Patients with high expression of HSPA5, YAP, and TAZ exhibited significantly poorer overall survival. Collectively, our findings suggested that HSPA5 promotes PMT through the stabilization of YAP/TAZ and identified HSPA5 as a promising therapeutic target for GBM patients.