TAZ mediates enhancer reprogramming blocks neuronal differentiation in glioma stem-like cells
Alessandra Audia1, Mahinur Mattohti2,3, Visweswaran Ravikumar4,5
1Department of Translational Molecular Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA.
Abstract:
Brain tumors such as glioblastomas contain hierarchically organized, tumor-propagating glioma stem-like cells (GSCs). A non-cytotoxic strategy to limit the growth of these cells involves promoting terminal differentiation and mitotic exit; however, these approaches have remained largely unsuccessful. In this study, we combined in silico, in vitro, and in vivo methods to determine the influence of transcriptional coactivator with PDZ-binding motif (TAZ), an oncogenic transcription coactivator, in regulating cellular hierarchies in GSCs. We found that TAZ inhibits the neuronal lineage pathway in gliomas and GSCs, and that TAZ expression inversely correlates the master transcription factors (TFs) that drive neuronal fate. Overexpression of TAZ in GSCs disrupted neuronal differentiation by restructuring the enhancer landscape and downregulating essential master TFs associated with neurogenesis, such as OLIG2 and ASCL1. These effects were mediated by histone deacetylases 1 HDAC1). Knockdown of TAZ and its paralog YAP caused aberrant neuronal differentiation of GSCs. Thus, directed neuronal fate can be achieved by blocking TAZ/HDAC complexes, uncovering a novel mode of cellular differentiation that can be utilized as a non-cytotoxic therapeutic strategy for malignant gliomas.
Insights
Blocking TAZ/HDAC complexes promotes neuronal differentiation in glioma stem cells (GSCs). This novel strategy offers a non-cytotoxic therapeutic approach for malignant brain tumors.
Area of Science:
- Neuro-oncology
- Cancer Stem Cell Biology
- Transcriptional Regulation
Background:
- Malignant gliomas, including glioblastomas, harbor glioma stem-like cells (GSCs) that drive tumor propagation.
- Targeting GSCs via non-cytotoxic differentiation is a promising therapeutic strategy but has faced challenges.
- The role of transcriptional coactivator with PDZ-binding motif (TAZ) in GSC hierarchy and differentiation remains unclear.
Purpose of the Study:
- To investigate the role of TAZ in regulating GSC hierarchy and neuronal differentiation.
- To identify molecular mechanisms by which TAZ influences GSC fate.
- To explore TAZ inhibition as a potential non-cytotoxic therapeutic strategy for malignant gliomas.
Main Methods:
- Integrated in silico, in vitro, and in vivo approaches.
- Analysis of TAZ expression and its correlation with master neuronal transcription factors (TFs).
- Investigated the impact of TAZ/YAP modulation on GSC differentiation and enhancer landscape, including the role of histone deacetylase 1 (HDAC1).
Main Results:
- TAZ was found to inhibit the neuronal lineage pathway in gliomas and GSCs.
- TAZ overexpression disrupted neuronal differentiation by altering the enhancer landscape and downregulating key neurogenesis TFs (e.g., OLIG2, ASCL1).
- Knockdown of TAZ and YAP induced aberrant neuronal differentiation, with effects mediated by HDAC1.
Conclusions:
- TAZ plays a critical role in suppressing neuronal differentiation in GSCs.
- Blocking TAZ/histone deacetylase 1 (HDAC1) complexes represents a novel strategy to induce directed neuronal fate.
- This approach offers a promising non-cytotoxic therapeutic avenue for treating malignant gliomas by targeting GSCs.
