Blockage of glioma cell survival by truncated TEAD-binding domain of YAP
Wei Zhao1,2, Qiu-Feng Dong1, Li-Wen Li3
1Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, Shaanxi, China.
Background:
Gliomas are highly aggressive and lack of efficient targeted therapy. YAP, as a Hippo pathway downstream effector, plays a key role in promoting tumor development through the interaction with transcription factor TEAD on the NH3-terminal proline-rich domain. Therefore, targeting TEAD-interacting domain of YAP may provide a novel approach for the treatment of gliomas.
Materials And Methods:
We generated a truncated YAP protein which includes the TEAD-binding domain (YAPBD), and supposed YAPBD can interact with endogenous TEAD but lost the function to activate YAP target gene expressions. The association of YAP expression with the malignant characters of glioma tissues were determined by immunohistochemistry. TEAD-binding capacity of YAPBD was determined by co-immunoprecipitation. The cell proliferation and migration were determined by MTT assay, xenograft assay, wound healing assay and transwell assay, respectively. YAP target genes were detected by Western blot.
Results:
YAP was highly expressed in glioma tissues and associated with tumor malignancy. YAPBD could block the TEAD-YAP complex formation by competing with YAP binding to TEAD. YAPBD could inhibit glioma cell growth both in vitro and in vivo, through the induction of cell cycle arrest and apoptosis. The cell cycle-related gene cyclin D1 and c-myc, and anti-apoptotic gene Bcl-2, Bcl-xL and survivin were inhibited after YAPBD overexpression. Furthermore, YAPBD also decreased cell migration and invasion, and repressed epithelial-mesenchymal transition.
Conclusion:
YAPBD can block glioma cell survival and repress YAP-dependent gene expressions, indicating gene therapy which targets TEAD-YAP complex would be a potential and significant novel approach for human malignant gliomas.
Insights
Targeting the YAP-TEAD interaction with YAPBD inhibits glioma growth and malignancy. This approach offers a promising new gene therapy strategy for aggressive gliomas.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Gliomas are aggressive brain tumors lacking effective targeted therapies.
- The YAP-TEAD protein-protein interaction is crucial for glioma development.
- Targeting this interaction presents a novel therapeutic strategy.
Purpose of the Study:
- To investigate the therapeutic potential of a truncated YAP protein (YAPBD) that inhibits YAP-TEAD interaction.
- To assess YAPBD's efficacy in blocking glioma cell proliferation, migration, and survival.
Main Methods:
- Generated a YAPBD protein to disrupt YAP-TEAD complex formation.
- Assessed YAP expression correlation with glioma malignancy using immunohistochemistry.
- Evaluated YAPBD's effects on cell proliferation, migration, apoptosis, and gene expression in vitro and in vivo.
Main Results:
- YAP is highly expressed in gliomas and linked to malignancy.
- YAPBD effectively blocked YAP-TEAD complex formation.
- YAPBD inhibited glioma cell growth, induced apoptosis, and repressed migration and epithelial-mesenchymal transition.
Conclusions:
- YAPBD disrupts YAP-dependent gene expression and glioma cell survival.
- Targeting the TEAD-YAP complex via gene therapy is a promising approach for malignant gliomas.
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