The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma

Bhat, Krishna; Salazar, Katrina; Balasubramaniyan, Veerakumar; Wani, Khalida; Heathcock, Lindsey; Hollingsworth, Faith; James, Johanna D.; Gumin, Joy; Diefes, Kristin; 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; Aldape, Kenneth

doi:10.1101/gad.176800.111

Cited by 334 publications

(394 citation statements)

References 95 publications

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“…27 However, we did not find significant differences in the methylation status of WWTR1 and its paralogue YAP1 in endometrial carcinosarcoma and endometrioid endometrial carcinoma samples, suggesting that this modification is unlikely to control the expression of TAZ. Together, these data rule out the possibility that TAZ expression in endometrial carcinoma is regulated by gene amplification or promoter methylation as the most common or unique regulatory mechanisms.…”

Section: Discussioncontrasting

confidence: 55%

“…TAZ has been closely associated with a mesenchymal signature in glioblastomas, 27 and weak TAZ expression was correlated with CpG island hypermethylation in the WWTR1 promoter of low-grade gliomas. 27 However, we did not find significant differences in the methylation status of WWTR1 and its paralogue YAP1 in endometrial carcinosarcoma and endometrioid endometrial carcinoma samples, suggesting that this modification is unlikely to control the expression of TAZ.…”

Section: Discussionmentioning

confidence: 99%

“…18,27 We first analyzed the WWTR1 locus (3q25.1) in tissue microarray by fluorescence in situ hybridization in order to assess whether the WWTR1 gene was amplified in endometrial carcinoma. 18 We were unable to find WWTR1 amplification in any of the tumors examined and thus, we ruled out this as a possible influence on TAZ expression (Supplementary Figure 1).…”

Section: Taz Expression Is Associated To Anomalous Scribble Expressiomentioning

confidence: 99%

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A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

et al. 2015

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Although TAZ, the final effector of the Hippo pathway that modulates epithelial to mesenchymal transition and stemness, has been implicated in the development of different types of cancer, its role in endometrial cancer has not yet been studied. Thus, we evaluated the expression of TAZ in different types of endometrial cancer by immunohistochemistry. TAZ expression was detected in 76% of undifferentiated endometrial carcinomas, 54% of endometrial carcinosarcomas, 46% of endometrial serous carcinomas, 36% of grade 3 endometrioid carcinomas, and 18% of grade 1-2 endometrioid carcinomas, with statistically significant differences. We analyzed the WWTR1 gene that encodes TAZ by FISH and MassARRAY spectrometry, ruling out gene amplification and differential promoter methylation as the main mechanisms that modulate TAZ expression in endometrial tumors. However, we did detect a significant association between Scribble hypoexpression and delocalization with TAZ expression. Moreover, we demonstrated that TAZ promoted invasiveness, and it favored cell motility and tumor growth, in endometrial cancer cell lines. In addition, TAZ expression was associated with the transition from an epithelial to mesenchymal phenotype, both in vitro and in human tumors. Together, these data reveal a previously unknown role for TAZ and the Hippo pathway in the progression of aggressive subtypes of endometrial cancer. Modern Pathology (2015Pathology ( ) 28, 1492Pathology ( -1503 doi:10.1038/modpathol.2015 published online 18 September 2015 In developed countries, endometrial carcinoma is the most common malignant tumor of the female genital tract. 1 On the basis of epidemiological, clinical, pathological, and molecular features, endometrial carcinoma can be classified into at least two main categories: 2 type I estrogen-dependent carcinomas that account for 80-85% of cases and that are typically represented by low-grade (grade 1 and 2) endometrioid carcinomas, and type II endometrial carcinomas that are not estrogen dependent and that are mainly represented by a serous subtype but also by other high-grade histological tumors like clear cell or undifferentiated carcinomas. 2 In endometrial carcinoma, the epithelial to mesenchymal transition has been associated with high-grade and aggressive features. [3][4][5][6] Epithelial to

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Taz Expression Is Associated To Anomalous Scribble Expressiomentioning

confidence: 99%

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A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

et al. 2015

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“…It has not been tested whether TEAD family transcription factors play a role in TAZand YAP-mediated differentiation of MSCs. Although TEADs seem unnecessary according to the current model of TAZ and YAP in regulation of PPARγ and Runx activity, it has been reported that TAZ drives aberrant osteoblastic and chondrocytic differentiation of glioma stem cells in a TEADdependent manner (Bhat et al, 2011). Therefore, the ability of YAP and TAZ in directing MSC differentiation may not be an atypical TEAD-independent function, although again it awaits further confirmation.…”

Section: The Hippo Pathway Directs Mesenchymal Stem Cell Differentiationmentioning

confidence: 87%

“…However, it was unknown whether re-expression of E-cadherin completely reversed TAZ-induced EMT, especially the mesenchymal features, which might be more important to the function of TAZ in promoting CSC self-renewal. It was shown in non-epithelial glioma stem cells that TAZ is associated with the expression of mesenchymal markers and higher-grade gliomas, which are less differentiated (Bhat et al, 2011). One possibility is that TAZ is downstream of EMT-inducing transcription factors and upstream of EMT, as well as EMT-induced CSC self-renewal.…”

Section: The Hippo Pathway and Cancer Stem Cellsmentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

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EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

2017

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The epithelial‐to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment‐derived stimuli that provoke EMT‐like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal‐to‐epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets.

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The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma

Cited by 334 publications

References 95 publications

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

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