The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma

Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Genes & development (Impact Factor: 10.8). 12/2011; 25(24):2594-609. DOI: 10.1101/gad.176800.111
Source: PubMed


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.

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Available from: Frederick F Lang, Oct 04, 2015
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    • "TAZ, as the paralog of YAP, has similar functions to YAP. TAZ increases the expression of several genes that promotes mesenchymal differentiation in malignant glioma [18]. As a result, the cells lose their epithelial properties including presence of polarity, intercellular junctions, and acquire mesenchymal or stem cell-like properties. "
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    ABSTRACT: Purpose: Yes-associated protein (YAP) and PDZ-binding motif (TAZ) are two important effectors of Hippo pathway controlling the balance of organ size and carcinogenesis. Amphiregulin (AREG) is a member of the epidermal growth factor family, a direct target gene of YAP and TAZ. The role of these proteins in hepatocellular carcinoma (HCC) is unclear. Methods: The expression of YAP, TAZ, and AREG in HCC was analyzed by immunohistochemical staining. The level of secreted serum AREG was also assayed by enzyme-linked immunosorbent (ELISA) assay. Results: YAP, TAZ, and AREG were expressed in 69.2% (27/39), 66.7% (26/39), and 61.5% (24/39) of HCC patients. The expression of YAP was significantly correlated with Edmondson stage (P>0.05), serum AFP level (P>0.05), and HCC prognosis (P>0.05). AREG expression was also significantly correlated with Edmondson stage (P>0.05) and serum AFP level (P>0.05). In addition, the expression of serum AREG was higher than serum AFP in HCC patients. Further multivariate analysis showed that YAP expression was an independent prognostic factor that significantly affected the overall survival of HCC patients. Conclusions: YAP maybe an independent prognostic indicator for HCC patients and serum AREG may be a serological biomarker of HCC.
    Research Journal of Immunology 04/2014; 2014(12):261365. DOI:10.1155/2014/261365
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    • "Their overexpression follows the activation of WNT/β-catenin pathway and results in increased in vitro cell migration and invasion [23, 24]. It is likely that the high expression of mesenchymal genes in the mesenchymal subset of human GBMs [25] can be considered to be reminiscent of the EMT program [26] or that the aberrant activation of EMT factors during gliomagenesis can trigger the mesenchymal shift in GBM [27]. "
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    ABSTRACT: Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent.
    04/2014; 2014:725921. DOI:10.1155/2014/725921
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    • "Additionally, co-activators of PAX8 are increased in gliomas. Increased TAZ (transcriptional co-activator with PDZ-binding motif) is observed in the mesenchymal subtype of glioblastoma [40,41]. Furthermore, TAZ is reduced in proneural glioblastomas, which are usually ALT-positive tumours and those with reduced PAX8 positivity in the current study [41]. "
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    ABSTRACT: The molecular basis to overcome therapeutic resistance to treat glioblastoma remains unclear. The anti-apoptotic b cell lymphoma 2 (BCL2) gene is associated with treatment resistance, and is transactivated by the paired box transcription factor 8 (PAX8). In earlier studies, we demonstrated that increased PAX8 expression in glioma cell lines was associated with the expression of telomerase. In this current study, we more extensively explored a role for PAX8 in gliomagenesis METHODS: PAX8 expression was measured in 156 gliomas including telomerase-negative tumours, those with the alternative lengthening of telomeres (ALT) mechanism or with a non-defined telomere maintenance mechanism (NDTMM), using immunohistochemistry and quantitative PCR. We also tested the affect of PAX8 knockdown using siRNA in cell lines on cell survival and BCL2 expression RESULTS: Seventy-two percent of glioblastomas were PAX8-positive (80% telomerase, 73% NDTMM, and 44% ALT). The majority of the low-grade gliomas and normal brain cells were PAX8-negative. The suppression of PAX8 was associated with a reduction in both cell growth and BCL2, suggesting that a reduction in PAX8 expression would sensitise tumours to cell death. PAX8 is increased in the majority of glioblastomas and promoted cell survival. Because PAX8 is absent in normal brain tissue, it may be a promising therapeutic target pathway for treating aggressive gliomas.
    BMC Cancer 03/2014; 14(1):159. DOI:10.1186/1471-2407-14-159 · 3.36 Impact Factor
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