title: The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.
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.
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA. kbhat@mdanderson.org
authors.forename: Krishna P L
authors.initials: KP
authors.lastname: Bhat
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Salazar
authors.forename: Veerakumar
authors.initials: V
authors.lastname: Balasubramaniyan
authors.forename: Khalida
authors.initials: K
authors.lastname: Wani
authors.forename: Lindsey
authors.initials: L
authors.lastname: Heathcock
authors.forename: Faith
authors.initials: F
authors.lastname: Hollingsworth
authors.forename: Johanna D
authors.initials: JD
authors.lastname: James
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Diefes
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Alice
authors.initials: A
authors.lastname: Turski
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Azodi
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yang
authors.forename: Tiffany
authors.initials: T
authors.lastname: Doucette
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.forename: Sjef
authors.initials: S
authors.lastname: Copray
authors.forename: Brian D
authors.initials: BD
authors.lastname: Vaillant
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
mesh_terms: D000217:Acyltransferases; D000818:Animals; D001932:Brain Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000503:physiopathology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D000091262:TEA Domain Transcription Factors; C101205:TEAD2 protein, human; C486310:Tead2 protein, mouse; D014157:Transcription Factors; D000217:Acyltransferases; C486363:tafazzin protein, mouse; C108675:TAFAZZIN protein, human