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

  • Cell Death Dis. 2026 Feb 7;17(1):208. doi: 10.1038/s41419-026-08428-3.
Shikai Gui  #  1  2  3  4 ,  Wanli Yu  #  1  2  3  4 ,  Zhen Song  #  5 ,  Lunshan Peng  1  2  3  4 ,  Haitao Luo  1  2  3  4 ,  Kai Huang  1  2  3  4 ,  Juexian Xiao  1  2  3  4 ,  Jiabao Xie  1  2  3  4 ,  Shihao Cai  1  2  3  4 ,  Shengtao Yuan  6  7 ,  Zhennan Tao  8  9 ,  Zujue Cheng  10  11  12  13  14
Affiliations
  • 1. Department of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 2. Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China.
  • 3. JXHC key Laboratory of Neurological medicine, Nanchang University, Nanchang, Jiangxi, China.
  • 4. Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, China.
  • 5. Department of Ultrasound, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 6. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 7. China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 8. Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 9. Neurosurgical Institute, Nanjing University, Nanjing, Jiangsu, China.
  • 10. Department of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. [email protected].
  • 11. Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China. [email protected].
  • 12. JXHC key Laboratory of Neurological medicine, Nanchang University, Nanchang, Jiangxi, China. [email protected].
  • 13. Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, China. [email protected].
  • 14. Department of Neurosurgery, Central Hospital of Shangrao City, Shangrao, Jiangxi, China. [email protected].
  • # Contributed equally.
PMID: 41654508 DOI: 10.1038/s41419-026-08428-3
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.

Products