WWTR1

Gene Summary

Gene:WWTR1; WW domain containing transcription regulator 1
Aliases: TAZ
Location:3q23-q24
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:WW domain-containing transcription regulator protein 1
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (30)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Non-Small Cell Lung Cancer
  • Chromosome 3
  • Tumor Suppressor Proteins
  • Childhood Cancer
  • Young Adult
  • RNA Interference
  • Retinoic Acid
  • Cell Proliferation
  • Phosphoproteins
  • Intracellular Signaling Peptides and Proteins
  • Gene Rearrangement
  • Cancer Gene Expression Regulation
  • Adolescents
  • Tumor Markers
  • Neoplasm Proteins
  • Vascular Neoplasms
  • Transfection
  • Cell Movement
  • Bone Cancer
  • Translocation
  • Trans-Activators
  • Base Sequence
  • Gene Expression
  • RTPCR
  • Western Blotting
  • Cervical Cancer
  • Sequence Analysis, RNA
  • Signal Transduction
  • Signal Transducing Adaptor Proteins
  • Oncogene Fusion Proteins
  • Gene Fusion
  • Transcription Factors
  • FISH
  • Colorectal Cancer
  • Apoptosis
  • Immunohistochemistry
  • Calcium-Binding Proteins
  • Hemangioendothelioma, Epithelioid
  • Connective Tissue Growth Factor
  • Breast Cancer
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: WWTR1 (cancer-related)

Mo JS, Meng Z, Kim YC, et al.
Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway.
Nat Cell Biol. 2015; 17(4):500-10 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
YAP (Yes-associated protein) is a transcription co-activator in the Hippo tumour suppressor pathway and controls cell growth, tissue homeostasis and organ size. YAP is inhibited by the kinase Lats, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation. YAP induces gene expression by binding to the TEAD family transcription factors. Dysregulation of the Hippo-YAP pathway is frequently observed in human cancers. Here we show that cellular energy stress induces YAP phosphorylation, in part due to AMPK-dependent Lats activation, thereby inhibiting YAP activity. Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. AMPK-induced YAP inhibition can suppress oncogenic transformation of Lats-null cells with high YAP activity. Our study establishes a molecular mechanism and functional significance of AMPK in linking cellular energy status to the Hippo-YAP pathway.

Puls F, Niblett A, Clarke J, et al.
YAP1-TFE3 epithelioid hemangioendothelioma: a case without vasoformation and a new transcript variant.
Virchows Arch. 2015; 466(4):473-8 [PubMed] Related Publications
Epithelioid hemangioendothelioma is a rare vascular tumor of borderline malignancy characterized by recurrent WWTR1-CAMTA1 gene fusions in approximately 90 % of cases. In addition, a recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1 negative epithelioid hemangioendotheliomas. This subset has been reported as having a distinct morphology with more obvious vasoformation, voluminous eosinophilic cytoplasm, and TFE3 positivity on immunohistochemistry. We report a case of a YAP1-TFE3 translocated epithelioid hemangioendothelioma arising in a groin lymph node in a 29-year-old male. Plump spindle cell morphology and absence of vasoformation made correct diagnosis particularly difficult. Immunohistochemistry showed nuclear positivity for both ERG and TFE3, fluorescence in situ hybridization showed break apart for TFE3 and RT-PCR identified a YAP1 exon1 to TFE3 exon 6 transcript, a previously unreported fusion variant. Awareness of this solid morphology and variant fusion will aid in identification of future cases of this rare vascular tumor.

Chang C, Goel HL, Gao H, et al.
A laminin 511 matrix is regulated by TAZ and functions as the ligand for the α6Bβ1 integrin to sustain breast cancer stem cells.
Genes Dev. 2015; 29(1):1-6 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Understanding how the extracellular matrix impacts the function of cancer stem cells (CSCs) is a significant but poorly understood problem. We report that breast CSCs produce a laminin (LM) 511 matrix that promotes self-renewal and tumor initiation by engaging the α6Bβ1 integrin and activating the Hippo transducer TAZ. Although TAZ is important for the function of breast CSCs, the mechanism is unknown. We observed that TAZ regulates the transcription of the α5 subunit of LM511 and the formation of a LM511 matrix. These data establish a positive feedback loop involving TAZ and LM511 that contributes to stemness in breast cancer.

Yuan J, Xiao G, Peng G, et al.
MiRNA-125a-5p inhibits glioblastoma cell proliferation and promotes cell differentiation by targeting TAZ.
Biochem Biophys Res Commun. 2015; 457(2):171-6 [PubMed] Related Publications
Glioblastoma (GBM) is the most lethal brain tumor due to the resistance to conventional therapies, such as radiotherapy and chemotherapy. TAZ, an important mediator of the Hippo pathway, was found to be up-regulated in diverse cancers, including in GBM, and plays important roles in tumor initiation and progression. However, little is known about the regulation of TAZ expression in tumors. In this study, we found that miR-125a-5p is an important regulator of TAZ in glioma cells by directly targeting the TAZ 3' UTR. MiR-125a-5p levels are inversely correlated with that of TAZ in normal astrocytes and a panel of glioma cell lines. MiR-125a-5p represses the expression of TAZ target genes, including CTGF and survivin, and inhibits cell proliferation and induces the differentiation of GBM cells; whereas over-expression of TAZ rescues the effects of miR-125a-5p. This study revealed a mechanism for TAZ deregulation in glioma cells, and also demonstrated a tumor suppressor role of miR-125a-5p in glioblastoma cells.

Xiao H, Jiang N, Zhou B, et al.
TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma.
Cancer Sci. 2015; 106(2):151-9 [PubMed] Related Publications
The transcriptional coactivator with PDZ binding motif (TAZ) has been reported to be one of the nuclear effectors of Hippo-related pathways. TAZ is expressed in many primary tumors and could regulate many biological processes. However, little is known about the role of TAZ in hepatocellular carcinoma (HCC). In the current study, we show that TAZ regulates cellular proliferation and epithelial-mesenchymal transition (EMT) of HCC. TAZ is overexpressed in HCC tissues and cell lines and upregulation of TAZ correlates with a lower overall survival rate of HCC patients after hepatic resection. TAZ knockdown results in inhibition of cancer cell proliferation through decreases in expression of stem cell markers (OCT4, Nanog, and SOX2). Reduction in HCC cell migration and invasion is also evident through reversal of EMT by increases E-cadherin expression, decreases in N-cadherin, vimentin, Snail, and Slug expression, and suppression of MMP-2 and MMP-9 expression. In a xenograft tumorigenicity model, TAZ knockdown could effectively inhibit tumor growth and metastasis through reversal of the EMT pathway. In conclusion, TAZ is associated with the proliferation and invasiveness of HCC cells, and the TAZ gene may contribute to a novel therapeutic approach against HCC.

Maroni P, Matteucci E, Drago L, et al.
Hypoxia induced E-cadherin involving regulators of Hippo pathway due to HIF-1α stabilization/nuclear translocation in bone metastasis from breast carcinoma.
Exp Cell Res. 2015; 330(2):287-99 [PubMed] Related Publications
The present study deals with the molecular mechanisms involved in the regulation of E-cadherin expression under hypoxia, because the adjustment of the amount of E-cadherin due to physical stimuli of the microenvironment might influence the colonization of metastasis to skeleton. We analyzed the effect of 1% oxygen tension, that is similar to that encountered in the bone marrow by metastatic cells spreading from breast carcinoma. The purpose was to evaluate the hypoxia-orchestrated control of E-cadherin transactivation via hypoxia inducible factor-1 (HIF-1) and peroxisome proliferator activated receptor-γ (PPARγ), and the involvement of Hippo pathway members, as regulators of transcription factors. To give a translational significance to the study, we took into consideration human pair-matched ductal breast carcinoma and bone metastasis: E-cadherin and Wwox were expressed in bone metastasis but not in breast carcinoma, while HIF-1α and TAZ seemed localized principally in nuclei of metastasis and were found in all cell compartments of breast carcinoma. A close examination of the regulatory mechanisms underlying E-cadherin expression in bone metastasis was done in 1833 clone derived from MDA-MB231 cells. Hypoxia induced E-cadherin only in 1833 clone, but not in parental cells, through HIF-1 and PPARγ activities, while Wwox decreased. Since Wwox was highly expressed in bone metastasis, the effect of ectopic Wwox was evaluated, and we showed E-cadherin transactivation and enhanced invasiveness in WWOX transfected 1833 cells. Also, hypoxia was additive with ectopic Wwox remarkably enhancing HIF-1α nuclear shuttle and accumulation due to the lengthening of the half-life of HIF-1α protein; under this experimental condition HIF-1α appeared as a slower migrated band compared with control, in agreement with the phosphorylation state. The in vitro data strongly supported the almost exclusive presence of HIF-1α in nuclei of human-bone metastasis. Thus, we identified Wwox as a novel molecule in the HIF-1α-HDM2 regulatory loop, necessary for the dynamic regulation of the HIF-1α amount, and we suggested that the reduction of endogenous Wwox free pool under hypoxia might also be due to the interaction with HDM2, sequestering the E3 ubiquitin ligase. We highlighted the importance of nuclear HIF-1α in the biology of metastasis for the mesenchymal-epithelial transition: this phenotype was regulated by Wwox plus hypoxia through E-cadherin target gene, playing a pivotal role in bone metastasis colonization.

Anderson T, Zhang L, Hameed M, et al.
Thoracic epithelioid malignant vascular tumors: a clinicopathologic study of 52 cases with emphasis on pathologic grading and molecular studies of WWTR1-CAMTA1 fusions.
Am J Surg Pathol. 2015; 39(1):132-9 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Malignant thoracic epithelioid vascular tumors are an uncommon and heterogenous group of tumors that include low-grade to intermediate-grade epithelioid hemangioendothelioma (EHE) and high-grade epithelioid angiosarcoma (EAS). We examine the morphologic and immunohistochemical features of 52 malignant epithelioid vascular tumors (10 low-grade EHE, 29 intermediate-grade EHE, and 13 EAS) involving the thorax (lung, pleura, mediastinum, heart, great vessels) including cases with exclusively thoracic disease (35) and with multiorgan disease including the thorax (17). Intermediate-grade EHE differs from low-grade EHE by the presence of necrosis, increased mitotic activity, and increased atypia. Morphologic features such as intranuclear inclusions, intracytoplasmic vacuoles, and stromal changes (chondroid, myxoid, or hyalinized stroma) are seen more frequently in EHE, whereas blood lakes, proliferation of slit-like vessels, and prominent nucleoli favor EAS. Fluorescence in situ hybridization analysis showed CAMTA1-WWTR1 fusions in 4/7 low-grade and 23/23 intermediate-grade EHE (P<0.001). In EAS, CAMTA1 rearrangement was negative in all cases, whereas a WWTR1 complex abnormality was found in 1/5 cases (P<0.001). This offers an objective means of differentiating intermediate-grade EHE from EAS, especially on limited biopsies. All cases show expression of at least 1 vascular marker, which allows differentiation from primary thoracic epithelial malignancies, although keratin expression is a potential pitfall with 29% of EHE and 25% of EAS showing keratin expression. Survival analysis shows that higher tumor grade for all tumors (P=0.026) as well as lung and pleural tumors only (P=0.010) and the presence of pleural involvement in lung and/or pleural tumors (P=0.042) correlate with poor prognosis.

Yusıflı Z, Kösemehmetoğlu K
CAMTA1 immunostaining is not useful in differentiating epithelioid hemangioendothelioma from its potential mimickers.
Turk Patoloji Derg. 2014; 30(3):159-65 [PubMed] Related Publications
OBJECTIVE: Epithelioid hemangioendothelioma is a rare member of vascular tumors of intermediate malignancy. Recently, presence of t(1;3) translocation and WWTR1/CAMTA1 gene fusion, which enhances CAMTA1 expression, are found to be specific to this tumor. We investigated the CAMTA1 immune expression profile of epithelioid hemangioendothelioma and its potential mimickers using a commercially available CAMTA1 antibody.
MATERIAL AND METHOD: Standard whole sections from the formalin fixed, paraffin embedded blocks of 12 epithelioid hemangioendotheliomas, 10 angiosarcomas, 9 epithelioid sarcomas, 8 malignant melanomas, 8 signet ring carcinomas, 7 lobular carcinomas of breast, 2 epithelioid mesotheliomas, 2 rhabdoid tumors and 12 miscellaneous hemangiomas were immunostained for anti-CAMTA1 (ab64119, 1:200; Abcam) after pretreatment with citrate pH 6.0 for 20 minutes using Leica Bond detection kit with DAB chromogen. Strong nuclear CAMTA1 expression was scored for its extent as 'negative' ( < 5% positive), '+1' (5-25% positive), '2+' (25-50% positive) and '3+' ( > 50% positive).
RESULTS: In 60 out of 70 cases (86%) either 2+ or 3+ strong nuclear staining was seen. Eighty-three % of epithelioid hemangioendotheliomas, 100% of angiosarcomas, 89% of epithelioid sarcomas, 89% of malignant melanomas, 63% of signet ring carcinomas, 71% of lobular carcinomas of breast, 100% of epithelioid mesotheliomas, 50% of rhabdoid tumors and 100% of hemangiomas were stained. Besides neurons, CAMTA1 expression was also observed in squamous epithelium, skin adnexa, breast lobules, prostate glands, bile ducts, colonic mucosa and gastric pits.
CONCLUSION: Epithelioid hemangioendothelioma, its potential morphological mimickers and other benign or malignant vascular tumors showed strong and diffuse CAMTA1 expression, nullifying the potential use of CAMTA1 immunohistochemistry as an adjunct in the differential diagnosis.

Wackerhage H, Del Re DP, Judson RN, et al.
The Hippo signal transduction network in skeletal and cardiac muscle.
Sci Signal. 2014; 7(337):re4 [PubMed] Related Publications
The discovery of the Hippo pathway can be traced back to two areas of research. Genetic screens in fruit flies led to the identification of the Hippo pathway kinases and scaffolding proteins that function together to suppress cell proliferation and tumor growth. Independent research, often in the context of muscle biology, described Tead (TEA domain) transcription factors, which bind CATTCC DNA motifs to regulate gene expression. These two research areas were joined by the finding that the Hippo pathway regulates the activity of Tead transcription factors mainly through phosphorylation of the transcriptional coactivators Yap and Taz, which bind to and activate Teads. Additionally, many other signal transduction proteins crosstalk to members of the Hippo pathway forming a Hippo signal transduction network. We discuss evidence that the Hippo signal transduction network plays important roles in myogenesis, regeneration, muscular dystrophy, and rhabdomyosarcoma in skeletal muscle, as well as in myogenesis, organ size control, and regeneration of the heart. Understanding the role of Hippo kinases in skeletal and heart muscle physiology could have important implications for translational research.

Yan L, Cai Q, Xu Y
Hypoxic conditions differentially regulate TAZ and YAP in cancer cells.
Arch Biochem Biophys. 2014; 562:31-6 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
The Hippo-YAP pathway is altered and implicated as an oncogenic signaling pathway in many human cancers. Hypoxia is an important microenvironmental factor that promotes tumorigenesis. However, the effects of hypoxia on the two most important Hippo-YAP effectors, YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), have not been reported. In this work, we demonstrated that TAZ was functionally involved in cell proliferation and/or migration in epithelial ovarian cancer (EOC) or human ovarian surface epithelial (HOSE) cells. Hypoxic conditions (1% O2 or hypoxia mimics) induced a reduction of YAP phosphorylation (S127) and total YAP expression in EOC cell lines OVCAR5 and SKOV3. However, these conditions up-regulated levels of S69 phosphorylated TAZ in EOC cells. The known TAZ kinases, Lats1 and Akt, were unlikely to be involved in up-regulated pTAZ by hypoxic conditions. Together, our data revealed new and differential regulating mechanisms of TAZ and YAP in cancer cells by hypoxia conditions.

Antonescu CR, Chen HW, Zhang L, et al.
ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features.
Genes Chromosomes Cancer. 2014; 53(11):951-9 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Epithelioid hemangioma (EH) is a benign neoplasm with distinctive vasoformative features, which occasionally shows increased cellularity, cytologic atypia, and/or loco-regional aggressive growth, resulting in challenging differential diagnosis from malignant vascular neoplasms. Based on two intraosseous EH index cases with worrisome histologic features, such as the presence of necrosis, RNA sequencing was applied for possible fusion gene discovery and potential subclassification of a novel atypical EH subset. A ZFP36-FOSB fusion was detected in one case, while a WWTR1-FOSB chimeric transcript in the other, both were further validated by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). These abnormalities were then screened by FISH in 44 EH from different locations with seven additional EH revealing FOSB gene rearrangements, all except one being fused to ZFP36. Interestingly, 4/6 penile EH studied showed FOSB abnormalities. Although certain atypical histologic features were observed in the FOSB-rearranged EH, including solid growth, increased cellularity, mild to moderate nuclear pleomorphism, and necrosis in 3/9 cases, no overt sarcomatous areas were discerned to objectively separate the lesions from the fusion-negative EH. No patient has developed recurrence to date, but the follow-up was relatively limited and short to draw definitive conclusions regarding behavior. Although FOSB-rearranged EH do not show significant morphologic overlap with SERPINE1-FOSB fusion-positive pseudomyogenic hemangioendothelioma, FOSB oncogenic activation is emerging as an important event in these benign and intermediate groups of vascular tumors.

Flucke U, Vogels RJ, de Saint Aubain Somerhausen N, et al.
Epithelioid Hemangioendothelioma: clinicopathologic, immunhistochemical, and molecular genetic analysis of 39 cases.
Diagn Pathol. 2014; 9:131 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
BACKGROUND: Epithelioid hemangioendothelioma is a malignant, often indolent vascular tumor which occurs at various anatomic sites. Based on a reciprocal translocation t (1;3)(p36;q25), a consistent WWTR1-CAMTA1 fusion gene has been found. An alternate YAP1-TFE3 fusion has been detected in a small and distinct subset of cases.
METHODS: Thirty-nine tumors, from 24 females and 15 males with an age range 9-85 years, were located in soft tissue (head and neck [8], trunk [5], upper extremities [3], lower extremities [2], mediastinal [1], and paratesticular [1]), lymph node (1), breast (1), skin (2), bone (6), lung (7), and liver (2). The cases were investigated using a panel of immunohistochemical markers. The aforementioned fusion-genes were examined using RT-PCR and/or FISH in order to validate their diagnostic value.
RESULTS: Follow-up available for 17 patients ranged from 3 months to 7 years (median interval 1.5 years). Eleven patients were alive without disease, 2 patients were alive with disease after 1.5 and 2 years, respectively. Four patients died of disease after 4 months (n = 1), 5 months (n = 2), and 1.5 years (n = 1).The size, known for 30 lesions, was >3 cm in 9 of them. Histologically, all lesions had classical features, at least focally. Four tumors counted >3 mitoses/50 HPF. Immunohistochemically, all cases tested stained positive for ERG (21), FLI1 (5) and CD31 (39). CD34 and D2-40 positivity was seen in 81% and 71% of the examined cases, respectively. 11/35 cases expressed pan-keratin and 6/20 cases CK8.18. TFE3 showed a nuclear reaction in 21/24 cases, irrespective of TFE3 rearrangement.Molecular genetically, 35/35 cases revealed one of the fusion genes by FISH and/or RT-PCR with WWTR1-CAMTA1 in 33 cases and YAP1-TFE3 in 2 cases.
CONCLUSIONS: These results demonstrate the high diagnostic value of FISH and RT-PCR in detecting the fusion genes of EHE. The immunohistochemical utility of TFE3 appears questionable in this study.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4010279141259481.

Liang K, Zhou G, Zhang Q, et al.
Expression of hippo pathway in colorectal cancer.
Saudi J Gastroenterol. 2014 May-Jun; 20(3):188-94 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
BACKGROUND/AIMS: Hippo pathway plays a crucial role in cell proliferation, apoptosis, and tumorigenesis. This study aimed to investigate the expression of Hippo pathway components in the progression and metastasis of colorectal cancer (CRC).
MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the mRNA expression levels of MST1, LATS2, YAP, TAZ, TEAD1, CDX2, and OCT4, and western blot (WB) was used to examine the protein expression levels of MST1, YAP, TEAD1, and CDX2 in 30 specimens of human colorectal adenomas, 50 pairs of human CRC tissues, and adjacent nontumorous tissues from CRC patients. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as the housekeeping gene in qRT-PCR.
RESULTS: The mRNA expression levels of MST1 and LATS2 showed an increasing tendency from CRC to adjacent nontumorous tissues (P < 0.001). Conversely, the mRNA expression levels of YAP, TAZ, TEAD, and OCT4 showed a decreasing tendency from CRC to adjacent nontumorous tissues (P < 0.001). MST1 protein was downregulated and YAP and TEAD1 proteins were upregulated in CRC (all P < 0.001). The mRNA and protein expression levels of CDX2 in CRC were significantly lower than those in colorectal adenomas and adjacent nontumorous tissues (P < 0.001), but there was no significant difference between the latter two groups (qRT-PCR, P = 0.113; WB, P = 0.151). Furthermore, statistical analysis showed that the expression levels of Hippo signal pathway components were associated with tumor differentiation, lymph node metastasis, and TNM stage.
CONCLUSION: Hippo pathway is suppressed in the progression from colorectal adenomas to CRC and is associated with CRC progression and metastasis. This study suggests the components of Hippo pathway might be prognostic indicators for CRC patients.

Noguchi S, Saito A, Horie M, et al.
An integrative analysis of the tumorigenic role of TAZ in human non-small cell lung cancer.
Clin Cancer Res. 2014; 20(17):4660-72 [PubMed] Related Publications
PURPOSE: TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (NSCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis.
EXPERIMENTAL DESIGN: We characterized TAZ at the DNA (n=192), mRNA (n=196), and protein levels (n=345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta-analysis of public datasets (n=1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ-dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis.
RESULTS: Higher TAZ mRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway.
CONCLUSION: TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies.

Castilla MÁ, López-García MÁ, Atienza MR, et al.
VGLL1 expression is associated with a triple-negative basal-like phenotype in breast cancer.
Endocr Relat Cancer. 2014; 21(4):587-99 [PubMed] Related Publications
Vestigial-like 1 (VGLL1) is a poorly characterized gene encoding a transcriptional co-activator structurally homologous to TAZ and YAP that modulates the Hippo pathway in Drosophila. In this study, we examined the expression of VGLL1 and its intronic miRNA, miR-934, in breast cancer. VGLL1 and miR-934 expression miRNA profiling was carried out on frozen samples of grade 3 invasive ductal carcinomas. VGLL1 protein was also examined in 433 sporadic and BRCA1-associated breast carcinomas on tissue microarrays. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to confirm differences in VGLL1 and miR-934 expression in different breast cancer subtypes, and to correlate their expression with that of other genes and miRNAs. Of 28 miRNAs differentially expressed in estrogen receptor (ER)-positive and ER-negative grade 3 breast carcinomas, miR-934 was most strongly upregulated in ER-negative carcinomas, and its expression was correlated with that of VGLL1. Nuclear VGLL1 expression was observed in 13% of sporadic breast carcinomas, and while VGLL1 was only occasionally found in luminal A (0.70%) and B (5.60%) carcinomas, it was often expressed in HER2-positive (17%), triple-negative (TN) breast carcinomas (>40%) and BRCA1-associated TN carcinomas (>50%). These findings were confirmed in the TCGA dataset, which revealed positive associations with luminal progenitor genes (GABRP, SLC6A14, FOXC1, PROM1, and BBOX1) and strong negative correlations with ER-associated genes (ESR1, C6ORF211, GATA3, and FOXA1). Moreover, VGLL1 expression was associated with reduced overall survival. In conclusion, VGLL1 and miR-934 are mainly expressed in sporadic and BRCA1-associated TN basal-like breast carcinomas, and their coordinated expression, at least partially mediated by the direct modulation of ESR1, might be involved in the maintenance of a luminal progenitor phenotype.

Han SX, Bai E, Jin GH, et al.
Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma.
J Immunol Res. 2014; 2014:261365 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
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.

Pathak S, Meng WJ, Zhang H, et al.
Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.
PLoS One. 2014; 9(5):e98317 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
BACKGROUND: Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial of preoperative RT.
METHODS: 140 rectal cancer patients were included in this study, of which 65 received RT before surgery and the rest underwent surgery alone. TAZ expression was determined by immunohistochemistry in primary cancer, distant, adjacent normal mucosa and lymph node metastasis. In-silico protein-protein interaction analysis was performed to study the predictive functional interaction of TAZ with other oncoproteins.
RESULTS: TAZ showed stronger expression in primary cancer and lymph node metastasis compared to distant or adjacent normal mucosa in both non-RT and RT patients. Strong TAZ expression was significantly higher in stages I-III and non-mucinious cancer of non-RT patients. In RT patients, strong TAZ expression in biopsy was related to distant recurrence, independent of gender, age, stages and grade (p = 0.043, HR, 6.160, 95% CI, 1.063-35.704). In silico protein-protein interaction study demonstrated that TAZ was positively related to oncoproteins, Livin, MAC30 and FXYD-3.
CONCLUSIONS: Strong expression of TAZ protein seems to be related to rectal cancer development and RT response, it can be a predictive biomarker of distant recurrence in patients with preoperative RT.

Zhao Y, Khanal P, Savage P, et al.
YAP-induced resistance of cancer cells to antitubulin drugs is modulated by a Hippo-independent pathway.
Cancer Res. 2014; 74(16):4493-503 [PubMed] Related Publications
Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients.

Hiemer SE, Szymaniak AD, Varelas X
The transcriptional regulators TAZ and YAP direct transforming growth factor β-induced tumorigenic phenotypes in breast cancer cells.
J Biol Chem. 2014; 289(19):13461-74 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Uncontrolled transforming growth factor-β (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here, we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs, and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in nontumorigenic cells to overcome TGFβ-repressive effects. Our work thus identifies cross-talk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms.

Yu FX, Guan KL
Transcription and processing: multilayer controls of RNA biogenesis by the Hippo pathway.
EMBO J. 2014; 33(9):942-4 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
The Hippo pathway plays a critical role in organ size control and tumorigenesis. YAP (and also its homologue TAZ) is a transcription co-activator that mediates the biological functions of the Hippo pathway. YAP activity is inhibited upon phosphorylation by the Lats kinases (reviewed in Yu & Guan, 2013). In a recent study in Cell, Mori et al (2014) uncover a new function of YAP in global microRNA (miRNA) biogenesis by the modulation of the Microprocessor machinery. The results also suggest that this novel YAP function may contribute to cell growth control and tumorigenesis.

Skibinski A, Breindel JL, Prat A, et al.
The Hippo transducer TAZ interacts with the SWI/SNF complex to regulate breast epithelial lineage commitment.
Cell Rep. 2014; 6(6):1059-72 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Lineage-committed cells of many tissues exhibit substantial plasticity in contexts such as wound healing and tumorigenesis, but the regulation of this process is not well understood. We identified the Hippo transducer WWTR1/TAZ in a screen of transcription factors that are able to prompt lineage switching of mammary epithelial cells. Forced expression of TAZ in luminal cells induces them to adopt basal characteristics, and depletion of TAZ in basal and/or myoepithelial cells leads to luminal differentiation. In human and mouse tissues, TAZ is active only in basal cells and is critical for basal cell maintenance during homeostasis. Accordingly, loss of TAZ affects mammary gland development, leading to an imbalance of luminal and basal populations as well as branching defects. Mechanistically, TAZ interacts with components of the SWI/SNF complex to modulate lineage-specific gene expression. Collectively, these findings uncover a new role for Hippo signaling in the determination of lineage identity through recruitment of chromatin-remodeling complexes.

Bartucci M, Dattilo R, Moriconi C, et al.
TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.
Oncogene. 2015; 34(6):681-90 [PubMed] Related Publications
Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.

Lau AN, Curtis SJ, Fillmore CM, et al.
Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis.
EMBO J. 2014; 33(5):468-81 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease.

Antonescu C
Malignant vascular tumors--an update.
Mod Pathol. 2014; 27 Suppl 1:S30-8 [PubMed] Related Publications
Although benign hemangiomas are among the most common diagnoses amid connective tissue tumors, sarcomas showing endothelial differentiation (ie, angiosarcoma and epithelioid hemangioendothelioma) represent under 1% of all sarcoma diagnoses, and thus it is likely that fewer than 500 people in the United States are affected each year. Differential diagnosis of malignant vascular tumors can be often quite challenging, either at the low end of the spectrum, distinguishing an epithelioid hemangioendothelioma from an epithelioid hemangioma, or at the high-grade end of the spectrum, between an angiosarcoma and a malignant epithelioid hemangioendothelioma. Within this differential diagnosis both clinico-radiological features (ie, size and multifocality) and immunohistochemical markers (ie, expression of endothelial markers) are often similar and cannot distinguish between benign and malignant vascular lesions. Molecular ancillary tests have long been needed for a more objective diagnosis and classification of malignant vascular tumors, particularly within the epithelioid phenotype. As significant advances have been recently made in understanding the genetic signatures of vascular tumors, this review will take the opportunity to provide a detailed update on these findings. Specifically, this article will focus on the following aspects: (1) pathological and molecular features of epithelioid hemangioendothelioma, including the more common WWTR1-CAMTA1 fusion, as well as the recently described YAP1-TFE3 fusion, identified in a morphological variant of epithelioid hemangioendothelioma; (2) discuss the heterogeneity of angiosarcoma clinical, morphological and genetic spectrum, with particular emphasis of MYC and FLT4 gene amplification in radiation-induced angiosarcoma; and (3) provide a practical guide in the differential diagnosis of epithelioid vascular tumors using molecular testing.

Shimomura T, Miyamura N, Hata S, et al.
The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity.
Biochem Biophys Res Commun. 2014; 443(3):917-23 [PubMed] Related Publications
YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP's functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP's co-activation of TEAD-mediated CTGF transcription.

Marastoni S, Andreuzzi E, Paulitti A, et al.
EMILIN2 down-modulates the Wnt signalling pathway and suppresses breast cancer cell growth and migration.
J Pathol. 2014; 232(4):391-404 [PubMed] Related Publications
EMILIN2 is an extracellular matrix (ECM) protein that exerts contradictory effects within the tumour microenvironment: it induces apoptosis in a number of tumour cells, but it also enhances tumour neo-angiogenesis. In this study, we describe a new mechanism by which EMILIN2 attenuates tumour cell viability. Based on sequence homology with the cysteine-rich domain (CRD) of the Frizzled receptors, we hypothesized that EMILIN2 could affect Wnt signalling activation and demonstrate direct interaction with the Wnt1 ligand. This physical binding leads to decreased LRP6 phosphorylation and to the down-modulation of β-catenin, TAZ and their target genes. As a consequence, EMILIN2 negatively affects the viability, migration and tumourigenic potential of MDA-MB-231 breast cancer cells in a number of two- and three-dimensional in vitro assays. EMILIN2 does not modulate Wnt signalling downstream of the Wnt-Frizzled interaction, since it does not affect the activation of the pathway following treatment with the GSK3 inhibitors LiCl and CHIR99021. The interaction with Wnt1 and the subsequent biological effects require the presence of the EMI domain, as there is no effect with a deletion mutant lacking this domain. Moreover, in vivo experiments show that the ectopic expression of EMILIN2, as well as treatment with the recombinant protein, significantly reduce tumour growth and dissemination of cancer cells in nude mice. Accordingly, the tumour samples are characterized by a significant down-regulation of the Wnt signalling pathway. Altogether, these findings provide further evidence of the complex regulations governed by EMILIN2 in the tumour microenvironment, and they identify a key extracellular regulator of the Wnt signalling pathway.

Serrano I, McDonald PC, Lock F, et al.
Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase.
Nat Commun. 2013; 4:2976 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
One of the hallmarks of cancers is the silencing of tumour suppressor genes and pathways. The Hippo tumour suppressor pathway is inactivated in many types of cancers, leading to tumour progression and metastasis. However, the mechanisms of pathway inactivation in tumours remain unclear. Here we demonstrate that integrin-linked kinase (ILK) plays a critical role in the suppression of the Hippo pathway via phospho-inhibition of MYPT1-PP1, leading to inactivation of Merlin. Inhibition of ILK in breast, prostate and colon tumour cells results in the activation of the Hippo pathway components MST1 and LATS1 with concomitant inactivation of YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) transcriptional co-activators and TEAD-mediated transcription. Genetic deletion of ILK suppresses ErbB2-driven YAP/TAZ activation in mammary tumours, and its pharmacological inhibition suppresses YAP activation and tumour growth in vivo. Our data demonstrate a role for ILK as a multiple receptor proximal regulator of Hippo tumour suppressor pathway and as a cancer therapeutic target.

Johnson R, Halder G
The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment.
Nat Rev Drug Discov. 2014; 13(1):63-79 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators.

Zhou GX, Li XY, Zhang Q, et al.
Effects of the hippo signaling pathway in human gastric cancer.
Asian Pac J Cancer Prev. 2013; 14(9):5199-205 [PubMed] Related Publications
BACKGROUND/AIM: The Hippo signaling pathway is a newly discovered and conserved signaling cascade, which regulates organ size control by governing cell proliferation and apoptosis. This study aimed to investigate its effects in human gastric cancer.
METHODS: Tumor tissues (n=60), adjacent non-tumor tissues (n=60) and normal tissues (n=60) were obtained from the same patients with primary gastric cancer (GC). In addition, 70 samples of chronic atrophic gastritis (CAG) tissues were obtained from patients with intestinal metaplasia (IM) by endoscopic biopsy. Hippo signaling molecules, including Mst1, Lats1, YAP1, TAZ, TEAD1, Oct4 and CDX2, were determined by quantitative polymerase chain reaction (qPCR). Protein expression of Mst1, Lats1, YAP1, TEAD1 and CDX2 was assessed by immunohistochemistry and Western blotting.
RESULTS: Mst1, Lats1 and Oct4 mRNA expression showed an increasing tendency from GC tissues to normal gastric tissues, while the mRNA expression of YAP1, TAZ and TEAD1 was up-regulated (all P<0.01). Mst1 and Lats1 protein expression presented a similar trend with their mRNA expression. In addition, YAP1 and TEAD1 protein expression in GC was significantly higher than in the other groups (all P<0.01). CDX2 mRNA and protein expression in the CAG group were higher than in the other groups (all P<0.01). In GC, mRNA expression of Mst1, Lats1, Oct4, YAP1, TAZ, TEAD1 and CDX2 had a close correlation with lymphatic metastasis and tumor TNM stage (all P<0.01). Furthermore, protein expression of Mst1, Lats1 ,YAP1, TAZ, TEAD1 and CDX2 had a close correlation between each other (P<0.05).
CONCLUSION: The Hippo signaling pathway is involved in the development, progression and metastasis of human gastric cancer. Therefore, manipulation of Hippo signaling molecules may be a potential therapeutic strategy for gastric cancer.

Lee SE, Park HY, Kim S, et al.
Epithelioid hemangioendothelioma with extensive cystic change and CAMTA1 rearrangement.
Pathol Int. 2013; 63(10):502-5 [PubMed] Related Publications
Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm that has the ability to recur locally and metastasize. Thus, it is important to distinguish this tumor from other epithelioid vascular neoplasms. A 47-year-old man presented to our hospital with a pelvic mass with severe ischialgia and weight loss. Surgical resection was performed, and the mass was found to have dark red multiloculated cysts with hemorrhage and calcification. The histopathologic examination showed a central sclerotic, hypocellular zone and a peripheral cellular zone. Only the peripheral portion of the wall revealed nested tumor cells in light blue myxoid stroma. These tumors are typically composed of short strands or cords of bland epithelioid cells with occasional intracytoplasmic lumens embedded in a myxohyalinized stroma. The tumor cells were positive for CD31 and CD34 and negative for factor VIII-related antigen, CK (AE1/AE3) and S-100. The tumor nuclei showed distinct break-apart signals with individual green and/or red signals, indicating the presence of CAMTA1 rearrangement. In this study, we report a case of EHE that was difficult to diagnose based on histology alone. Therefore, we also performed fluorescence in situ hybridization, and found that the tumor harbored a CAMTA1 gene rearrangement, which confirmed the diagnosis.

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