TAZ mediates enhancer reprogramming blocks neuronal differentiation in glioma stem-like cells.
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.