The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma

Krishna P.L. Bhat; Katrina L. Salazar; Veerakumar Balasubramaniyan; Khalida Wani; Lindsey Heathcock; Faith Hollingsworth; Johanna D. James; Joy Gumin; Kristin L. Diefes; Se Hoon Kim; Alice Turski; Yasaman Azodi; Yuhui Yang; Tiffany Doucette; Howard Colman; Erik P. Sulman; Frederick F. Lang; Ganesh Rao; Sjef Copray; Brian D. Vaillant; Kenneth D. Aldape

doi:10.1101/gad.176800.111

The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma

¹Department of Pathology,
²Department of Neuro-Oncology,
³Department of Neurosurgery,
⁴Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
⁵Department of Neuroscience, University Medical Center Groningen, 9713 AV Groningen, The Netherlands

↵6 These authors contributed equally to this work.

↵Present addresses: ⁷Department of Pathology, College of Medicine, Yonsei University, Seoul 120-752, Korea;
↵8 Department of Neurosurgery, University of Utah, Salt Lake City, UT 84132, USA;
↵9 Huntsman Cancer Institute, Salt Lake City, UT 84132, USA;
↵10 The Methodist Hospital Neurological Institute, Houston, TX 77030, USA.

Abstract

Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.