Abstract
The transcriptional coactivator with PDZ-binding motif (TAZ) is one of the important downstream effectors of Hippo pathway. In this study, the potential implication of TAZ in gliomagenesis was explored. TAZ expression was identified to be upregulated in glioma specimens and positively correlated with tumor grade. Meanwhile, its expression in nucleus was increased more significantly with the ascending order of tumor grade. Knocking down TAZ inhibited glioma cell proliferation, invasion and promoted apoptosis. Conversely, enforced upregulation of TAZ promoted proliferation, invasion of glioma cells, and suppressed apoptosis in vitro. When orthotopic glioblastoma mouse model implanted with TAZ knocked down cells, glioma growth was inhibited and survival period was prolonged. Expression of Ki67, MMP-9, Cyclin D1, Bcl-2 and C-myc was varied in accordance with the level of TAZ in glioma cell. The biomarkers of EMT (epithelial-mesenchymal transition), vimentin and N-cadherin, were downregulated when TAZ was suppressed. Using Co-immunoprecipitation TAZ was identified to bind to TEAD4. Therefore, our findings indicate that TAZ is overexpressed in glioma and translocated more into nucleus in high grade glioma. TAZ is involved in gliomagenesis by promoting glioma growth and may benefit to EMT progression. This result suggests that TAZ serves as a potential target for the treatment of glioma.
Highlights
Glioma is the most common primary intracranial tumor, characterized by diffusely infiltrative growth and highly cellular heterogeneity associated with therapeutic resistance.The Hippo pathway was firstly discovered in Drosophila, and plays a key role in the regulation of organ size by controlling cell proliferation and apoptosis [1,2,3]
transcriptional coactivator with PDZ-binding motif (TAZ) is overexpressed in glioma specimens and correlates with tumor grade We defined the TAZ expression status in 41 glioma specimens and 3 nontumorous brain tissues
Quantitative PCR indicated that TAZ expression in 38 cases of 41 glioma tissues (92.68%) was increased than that in nontumorous brain tissues, and positively correlated with tumor grade (P
Summary
The Hippo pathway was firstly discovered in Drosophila, and plays a key role in the regulation of organ size by controlling cell proliferation and apoptosis [1,2,3]. TAZ (transcriptional co-activator with PDZ-binding motif) and its paralog, YAP (Yes-associated protein), are downstream effectors of Hippo pathway. The Hippo pathway inactivates TAZ by a series of phosphorylation events. Phosphorylated TAZ (p-TAZ) is maintained in the cytoplasm by interaction with 14-3-3 proteins or degraded via proteasome-targeted degradation. When Hippo pathway is inhibited, YAP and TAZ are translocated to the nucleus as transcriptional co-activators, TAZ binds with other transcription factors, such as TEADs, PPAR, RUNX2, etc and stimulates the transcription of its target genes to promote cell proliferation and EMT [4,5,6]
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