Abstract
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.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors would like to thank the Jiangxi Province Key Laboratory of Neurological Diseases for providing experimental and technical support.
Funding
This research was supported by the Chinese Academy of Medical Sciences (ZZ15-WT-04), the HealthChina·BuChang ZhiYuan Public welfare projects for heart and brain health underGrant (No. HIGHER2023099), the Health Commission of Jiangxi Province (No. 20208031 and No. 20204345), and National Natural Science Foundation of China (No. 82460526) to Zujue Cheng; the Health Commission of Jiangxi Province (No. YC2023-B094) and Incubation project of the Second Affiliated Hospital of Nanchang University (No. 2025YNFY12033) to Shikai Gui; National Natural Science Foundation of China (No. 82203876 and 82271363), Natural Science Foundation of basic research program of Jiangsu Province, Youth Program (BK20220184), China Postdoctoral Science Foundation--Special Funding (2022TQ0143), China Postdoctoral Science Foundation--General Support (2022M711587) to Zhennan Tao; National Natural Science Foundation of China (No. 82360475), and Incubation project of the Second Affiliated Hospital of Nanchang University (No. 2022YNFY12005) to Haitao Luo.
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Shikai Gui and Zujue Cheng conceived the project and designed the study. Shikai Gui, Wanli Yu, Zhen Song, Lunshan Peng, and Jiabao Xie conducted bioinformatics analyses and experiments. Haitao Luo, Zhennan Tao, and Shihao Cai collected the clinical tumor samples. Shengtao Yuan, Kai Huang, and Juexian Xiao provided technical assistance. Zujue Cheng discussed data and supervised the study. All authors performed data analysis and interpretation and had read and approved the final manuscript.
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The present study was approved by the Ethics Committee of the Affiliated Drum Tower Hospital of Nanjing University Medical School and was conducted in accordance with the Declaration of Helsinki. The animal experiments were approved by the Animal Welfare Ethical Review Committee of the Affiliated Drum Tower Hospital of Nanjing University Medical School.
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Gui, S., Yu, W., Song, Z. et al. HSPA5 promotes YAP/TAZ stability independently of the Hippo pathway and induces proneural-to-mesenchymal transition in glioblastoma. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08428-3
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DOI: https://doi.org/10.1038/s41419-026-08428-3
