Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase

Serrano, Isabel; McDonald, Paul C.; Lock, Frances E.; Muller, William J.; Dedhar, Shoukat

doi:10.1038/ncomms3976

Cited by 181 publications

(175 citation statements)

References 55 publications

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“…3, Supplementary Figure 2, see section on supplementary data given at the end of this article). This contrasts with results described in a recent report on glioblastoma, which indicated that TAZ expression correlated with the DNA methylation status of the promoter sequences (Bhat et al 2011 (Serrano et al 2013). In light of these results, it seems that enhanced TAZ protein expression in TN/basal breast cancer may result from post-transcriptional/translational regulatory mechanisms, although transcriptional regulation also clearly contributes to this process (Fig.…”

Section: Discussioncontrasting

confidence: 56%

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

Díaz‐Martín¹,

López-García²,

Romero‐Pérez³

et al. 2015

Endocrine-Related Cancer

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The Hippo signaling pathway, a conserved regulator of organ size, has emerged as an important regulatory pathway in cancer. The final transducer effectors of this pathway in mammals are the oncoproteins TAZ and YAP1, which are transcriptional coactivators of target genes involved in cell proliferation and survival. TAZ has been previously reported to play a role in tumorigenesis in breast cancer, but detailed analyses of the different breast cancer phenotypes have not been conducted thus far. We analyzed TAZ expression by immunohistochemistry in a retrospective series of 640 invasive breast carcinomas, comprising estrogen/progesterone receptor-positive (ERC/PRC), HER2-positive, and triple-negative (TN) tumors. We found a strong association of TAZ nuclear expression with the TN phenotype (60.5% TAZ-positive, P!0.001), which was strengthened when stratified into the basal-like subtype (70.8% TAZ-positive, P!0.001). Moreover, 90% of metaplastic breast carcinomas with morphological epithelial-mesenchymal transition features were TAZ-positive. We also investigated whether amplification or differential DNA methylation of the TAZ-encoding locus could account for the observed enhanced TAZ protein expression in the TN/basal phenotype. Amplification of the TAZ locus was analyzed by fluorescence in situ hybridization in 30 TN tumors, and we found gene amplification in some cases (6.45%). DNA methylation analysis was performed using the Sequenom MassArray MALDI-TOF platform, and we observed similar low methylation levels both in TN (nZ25) and ERC/PRC (nZ26) tumors. These results were further confirmed using a panel of breast cancer cell lines and using the TCGA dataset. Finally, patients with strong TAZ expression showed poorer clinical outcomes with respect to both recurrence and overall survival.

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Section: Discussioncontrasting

confidence: 56%

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

Díaz‐Martín¹,

López-García²,

Romero‐Pérez³

et al. 2015

Endocrine-Related Cancer

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“…Consistently, clinical studies have found convergent mutations in both ADC and SCC components from a single lesion of human Ad-SCC [35][36][37][38][39] , leading to the hypothesis that there exists dynamic cell lineage conversion between these two pathologically and morphologically distinct tumour subtypes. Our work in Lkb1-deficient mouse models has recently provided the first de novo evidences supporting this hypothesis 18 . It is worth noting that the ADC to SCC transdifferentiation is unlikely related to the classical cancer stem cell theory, in which only a small population of cancer cells were endowed with strong plasticity 32,33 .…”

Section: Discussionmentioning

confidence: 65%

“…Our recent data show that lung ADC with Lkb1 deficiency can progressively transdifferentiate into SCC in Kras G12D , Lkb1 L/L (KL) mouse model 21 and all the SCC in this model are indeed derived from ADC 18 . Integrative bioinformatic analyses on microarray data sets derived from Lkb1-deficient mouse ADC and SCC have identified a series of significantly deregulated signalling pathways among which the Hippo pathway, previously shown to regulate cell fate determination during early embryonic development and adult tissue regeneration, caught our attention.…”

Section: Resultsmentioning

confidence: 99%

“…This provides the first evidence to support the potential cell fate conversion implicated by the clinical observation of lung adenosquamous carcinoma (Ad-SCC), which contains mixed adenomatous and squamous pathologies with identical genetic alterations 18 . Lung ADC and SCC are two distinct lung cancer subtypes not only morphologically different but also featured with different gene expression signatures and cells of origin, for example, ADC is considered to arise mainly from alveolar epithelial cells such as type II pneumocytes with surfactant protein expression, whereas SCC is from basal cells with DNp63 expression 19,20 .…”

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confidence: 97%

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YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

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Whether the Hippo pathway contributes to cell lineage transition under pathological conditions, especially tumorigenesis, remains largely unknown. Here we show that YAP, the major effector of the Hippo pathway, displays a distinct activation pattern in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC); YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner. During transdifferentiation, YAP is inactivated, which in turn relieves ZEB2-mediated default repression of DNp63 and triggers squamous differentiation reprogramming. Disruption of the YAP barrier for phenotypic transition significantly accelerates squamous transdifferentiation, whereas constitutive YAP activation conversely inhibits this transition. More importantly, ectopic DNp63 expression rescues the inhibitory effect of YAP on squamous transdifferentiation. These findings have established YAP as an essential barrier for lung cancer cell fate conversion and provided a mechanism for regulating cancer plasticity, which might hold important implication for YAP-targeted therapies.

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“…S7B), suggesting the flow regulation of YAP/TAZ activities does not solely depend on LATS kinases but also through the modulation of Rho-GTPase activities. In addition to the Hippo and Rho-GTPase pathways, other known mechanosensors, such as G protein-coupled receptors and integrins (23,24), and mechanotransduction pathways, including AMP-activated protein kinase, and VE-cadherinmediated phosphatidylinositol 3-kinase (PI3K)/AKT signaling (25,26), have been shown to modulate YAP/TAZ activities through phosphorylation. It would be worthwhile to further delineate the Hippo signaling cascade and the cross-talk between the flow-sensitive pathways that modulate YAP/TAZ activities.…”

Section: Discussionmentioning

confidence: 99%

Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

Wang

Yeh

Nguyen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

331

325

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The focal nature of atherosclerotic lesions suggests an important role of local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechanotransduction and vascular homeostasis. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of atheroprone endothelial phenotypes and the consequential development of atherosclerotic lesions. We found that exposure of cultured endothelial cells (ECs) to the atheroprone disturbed flow resulted in YAP/TAZ activation and translocation into EC nucleus to up-regulate the target genes, including cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). In contrast, the atheroprotective laminar flow suppressed YAP/TAZ activities. En face analysis of mouse arteries demonstrated an increased nuclear localization of YAP/TAZ and elevated levels of the target genes in the endothelium in atheroprone areas compared with athero-protective areas. YAP/TAZ knockdown significantly attenuated the disturbed flow induction of EC proliferative and proinflammatory phenotypes, whereas overexpression of constitutively active YAP was sufficient to promote EC proliferation and inflammation. In addition, treatment with statin, an antiatherosclerotic drug, inhibited YAP/TAZ activities to diminish the disturbed flow-induced proliferation and inflammation. In vivo blockade of YAP/TAZ translation by morpholino oligos significantly reduced endothelial inflammation and the size of atherosclerotic lesions. Our results demonstrate a critical role of the activation of YAP/TAZ by disturbed flow in promoting atheroprone phenotypes and atherosclerotic lesion development. Therefore, inhibition of YAP/TAZ activation is a promising athero-protective therapeutic strategy.atherogenesis | disturbed flow | endothelial cells | mechanotransduction

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Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase

Cited by 181 publications

References 55 publications

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

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