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. VaillantKenneth D. Aldape

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2594-2609
Number of pages16
JournalGenes and Development
Volume25
Issue number24
DOIs
Publication statusPublished - 2011 Dec 15

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Glioma
Glioblastoma
Neoplasms
Neural Stem Cells
Atlases
Chromatin Immunoprecipitation
Mesenchymal Stromal Cells
Stem Cells
Genome
Survival
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Cite this

Bhat, K. P. L., Salazar, K. L., Balasubramaniyan, V., Wani, K., Heathcock, L., Hollingsworth, F., ... Aldape, K. D. (2011). The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes and Development, 25(24), 2594-2609. https://doi.org/10.1101/gad.176800.111
Bhat, Krishna P.L. ; Salazar, Katrina L. ; Balasubramaniyan, Veerakumar ; Wani, Khalida ; Heathcock, Lindsey ; Hollingsworth, Faith ; James, Johanna D. ; Gumin, Joy ; Diefes, Kristin L. ; Kim, Se Hoon ; Turski, Alice ; Azodi, Yasaman ; Yang, Yuhui ; Doucette, Tiffany ; Colman, Howard ; Sulman, Erik P. ; Lang, Frederick F. ; Rao, Ganesh ; Copray, Sjef ; Vaillant, Brian D. ; Aldape, Kenneth D. / The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. In: Genes and Development. 2011 ; Vol. 25, No. 24. pp. 2594-2609.
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abstract = "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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Bhat, KPL, Salazar, KL, Balasubramaniyan, V, Wani, K, Heathcock, L, Hollingsworth, F, James, JD, Gumin, J, Diefes, KL, Kim, SH, Turski, A, Azodi, Y, Yang, Y, Doucette, T, Colman, H, Sulman, EP, Lang, FF, Rao, G, Copray, S, Vaillant, BD & Aldape, KD 2011, 'The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma', Genes and Development, vol. 25, no. 24, pp. 2594-2609. https://doi.org/10.1101/gad.176800.111

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

In: Genes and Development, Vol. 25, No. 24, 15.12.2011, p. 2594-2609.

Research output: Contribution to journalArticle

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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

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AU - Vaillant, Brian D.

AU - Aldape, Kenneth D.

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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.

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Bhat KPL, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F et al. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes and Development. 2011 Dec 15;25(24):2594-2609. https://doi.org/10.1101/gad.176800.111