Inhibition of TAZ contributes radiation-induced senescence and growth arrest in glioma cells.

Abstract

Glioblastoma (GBM) is the most aggressive brain tumor and resistant to current available therapeutics, such as radiation. To improve the clinical efficacy, it is important to understand the cellular mechanisms underlying tumor responses to radiation. Here, we investigated long-term cellular responses of human GBM cells to ionizing radiation. Comparing to the initial response within 12 hours, gene expression modulation at 7 days after radiation is markedly different. While genes related to cell cycle arrest and DNA damage responses are mostly modulated at the initial stage; immune-related genes are specifically affected as the long-term effect. This later response is associated with increased cellular senescence and inhibition of transcriptional coactivator with PDZ-binding motif (TAZ). Mechanistically, TAZ inhibition does not depend on the canonical Hippo pathway, but relies on enhanced degradation mediated by the β-catenin destruction complex in the Wnt pathway. We further showed that depletion of TAZ by RNAi promotes radiation-induced senescence and growth arrest. Pharmacological activation of the β-catenin destruction complex is able to promote radiation-induced TAZ inhibition and growth arrest in these tumor cells. The correlation between senescence and reduced expression of TAZ as well as β-catenin also occurs in human gliomas treated by radiation. Collectively, these findings suggested that inhibition of TAZ is involved in radiation-induced senescence and might benefit GBM radiotherapy.

• Authors: Lei Zhang, Fangling Cheng, Yiju Wei, Lijun Zhang, Dongsheng Guo, Baofeng Wang, Wei Li
• Journal: Oncogene (Oncogene) Vol. 38 Issue 15 Pg. 2788-2799 (04 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30542117 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Axin Signaling Complex
• Intracellular Signaling Peptides and Proteins
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• WWTR1 protein, human
• beta Catenin

Topics

• Axin Signaling Complex (genetics)
• Brain Neoplasms (genetics, radiotherapy)
• Cell Cycle Checkpoints (genetics, radiation effects)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cellular Senescence (genetics)
• Gene Expression (genetics, radiation effects)
• Glioblastoma (genetics, radiotherapy)
• Glioma (genetics, radiotherapy)
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics)
• Radiation, Ionizing
• Radiotherapy (methods)
• Trans-Activators
• Transcription Factors (antagonists & inhibitors, genetics)
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• beta Catenin (genetics)