TY - JOUR
T1 - The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma
AU - Bhat, Krishna P.L.
AU - Salazar, Katrina L.
AU - Balasubramaniyan, Veerakumar
AU - Wani, Khalida
AU - Heathcock, Lindsey
AU - Hollingsworth, Faith
AU - James, Johanna D.
AU - Gumin, Joy
AU - Diefes, Kristin L.
AU - Kim, Se Hoon
AU - Turski, Alice
AU - Azodi, Yasaman
AU - Yang, Yuhui
AU - Doucette, Tiffany
AU - Colman, Howard
AU - Sulman, Erik P.
AU - Lang, Frederick F.
AU - Rao, Ganesh
AU - Copray, Sjef
AU - Vaillant, Brian D.
AU - Aldape, Kenneth D.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/12/15
Y1 - 2011/12/15
N2 - Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) geneexpression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis ofavailable expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified thetranscriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZexpression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG islandhypermethylation 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, overexpressionof TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression andaberrant 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 complexwith TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with plateletderivedgrowth 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.
AB - Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) geneexpression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis ofavailable expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified thetranscriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZexpression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG islandhypermethylation 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, overexpressionof TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression andaberrant 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 complexwith TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with plateletderivedgrowth 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.
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U2 - 10.1101/gad.176800.111
DO - 10.1101/gad.176800.111
M3 - Article
C2 - 22190458
AN - SCOPUS:84255160601
VL - 25
SP - 2594
EP - 2609
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 24
ER -