Abstract
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.
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Acknowledgements
This work was financially sponsored by grants from the National Natural Science Foundation of China (Nos. 81472358, 81172396) and the Social Development Key Project of Shaanxi Province (No. 2014K11-01-02-07).
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Zhao, W., Dong, Qf., Li, Lw. et al. Blockage of glioma cell survival by truncated TEAD-binding domain of YAP. J Cancer Res Clin Oncol 147, 1713–1723 (2021). https://doi.org/10.1007/s00432-021-03577-8
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DOI: https://doi.org/10.1007/s00432-021-03577-8