Overexpression Of TAZ Research Articles

The Hippo Coactivator TAZ Exacerbates Cisplatin-Induced Acute Renal Injury

Introduction: Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling pathway effector, maintains the balance of cell proliferation, differentiation, and death. However, the role of TAZ in tubular cell survival and acute kidney injury (AKI) remains largely unknown. Methods: We used the RNA-seq database, Western blot, and immunohistochemistry to examine TAZ expression in kidneys from cisplatin-induced AKI. We generated tubular-specific TAZ knockout mice to assess the role of TAZ in cisplatin-induced renal toxicity. Immunoprecipitation-mass spectrometry followed standard procedures. Results: TAZ was activated in tubular cells in kidneys injected with cisplatin. Conditional deletion of TAZ in tubular cells confers ferroptosis resistance and protects kidneys from cisplatin-induced AKI, whereas overexpression of TAZ(S89A) exacerbates cisplatin-induced ferroptosis. Inhibition of ferroptosis with ferrostatin-1 potently preserves renal function and alleviates morphological injury and tubular cell ferroptosis induced by cisplatin. Mechanistically, in a PPARδ-dependent manner, but not TEAD, TAZ reduces the expression of glutathione peroxidase 4 (GPX4), thus exacerbating cisplatin-induced ferroptosis. Conclusions: Our findings show that cisplatin-induced AKI and tubular cell ferroptosis are mediated by TAZ-PPARδ interaction through regulation of GPX4, highlighting TAZ as a potential therapeutic candidate for AKI.

Inhibition of Connective Tissue Growth Factor Expression in Adult Retinal Pigment Epithelial-19 Cells by Blocking Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Activity.

Purpose: To investigate the effect of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) on connective tissue growth factor (CTGF) expression in adult retinal pigment epithelial (ARPE)-19 cells. We also studied the inhibitory effect of K-975, a new pan-transcriptional enhanced associate domain (TEAD) inhibitor, and luteolin, a plant-derived flavonoid on CTGF expression. Methods: ARPE-19 cells were transfected with either YAP or TAZ overexpression plasmid or treated with transforming growth factor (TGF)-β2. The cells were cultured either with or without K-975 or luteolin. The expression of YAP, TAZ, and CTGF was examined using real-time PCR. Results: ARPE-19 cells overexpressing YAP or TAZ exhibited significantly increased CTGF expression. This increase was attenuated by K-975 or luteolin alone. TGF-β2 treatment significantly raised the expression of not just YAP and TAZ, but also CTGF in ARPE-19 cells. TGF-β2 treatment-enhanced CTGF expression was considerably lowered by the addition of K-975 or luteolin. Conclusions: Overexpression of YAP or TAZ and treatment with TGF-β2 led to an increase in the expression of CTGF in ARPE-19 cells. These increases were attenuated by treatment with K-975 and luteolin. These findings suggest that YAP and TAZ may be related to the expression of CTGF in ARPE-19 cells and that K-975 and luteolin can be explored as potential therapeutic agents for preventing CTGF production in vitreoretinal fibrosis.

IFT80 promotes early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.

Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation as the essential functional component of primary cilia. The effects of IFT80 on early bone healing of extraction sockets have not been well studied. To investigate whether deletion of Ift80 in alveolar bone-derived mesenchymal stem cells (aBMSCs) affected socket bone healing, we generated a mouse model of specific knockout of Ift80 in Prx1 mesenchymal lineage cells (Prx1Cre;IFT80f/f). Our results demonstrated that deletion of IFT80 in Prx1 lineage cells decreased the trabecular bone volume, ALP-positive osteoblastic activity, TRAP-positive osteoclastic activity, and OSX-/COL I-/OCN-positive areas in tooth extraction sockets of Prx1Cre; IFT80f/f mice compared with IFT80f/f littermates. Furthermore, aBMSCs from Prx1Cre; IFT80f/f mice showed significantly decreased osteogenic markers and downregulated migration and proliferation capacity. Importantly, the overexpression of TAZ recovered significantly the expressions of osteogenic markers and migration capacity of aBMSCs. Lastly, the local administration of lentivirus for TAZ enhanced the expression of RUNX2 and OSX and promoted early bone healing of extraction sockets from Prx1Cre; IFT80f/f mice. Thus, IFT80 promotes osteogenesis and early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.

Deregulation of the Hippo Signaling Pathway in Virus-Associated Cancer

"Hippo signaling has been recognized as a newly identified tumor suppressor signaling pathway that can regulate cellular processes including regeneration, cell death, differentiation, and development. Its dysregulation through overexpression of YAP (Yes-associated protein) and TAZ (PDZ-binding motif) as two main oncogenic factors of the Hippo pathway has a crucial role in several cancers. Because of the limited prognosis and therapeutic targets, further understanding of molecular pathways involved in tumorigenesis is one of the interesting issues in studies. Here, we demonstrated that some viruses, through dysregulation of the Hippo signaling pathway can be implicated in transformation, metastasis, and chemotherapeutic drug resistance in virus-related cancer and also help processes involved in the pathogenesis of viral infection such as persistence "

Retraction: Overexpression of YAP and TAZ Is an Independent Predictor of Prognosis in Colorectal Cancer and Related to the Proliferation and Metastasis of Colon Cancer Cells.

Retraction: Overexpression of YAP and TAZ Is an Independent Predictor of Prognosis in Colorectal Cancer and Related to the Proliferation and Metastasis of Colon Cancer Cells.

Wogonin Induces Cell Cycle Arrest and Apoptosis of Hepatocellular Carcinoma Cells by Activating Hippo Signaling.

Wogonin has been reported to exhibit pharmacological effects against cancer by regulating cell proliferation, metastasis and apoptosis, however, the role of wogonin in hepatocellular carcinoma (HCC) remains poorly elucidated. The current study aimed to illustrate whether wogonin influences HCC cell cycle progression and apoptosis by regulating Hippo signaling. The effects of wogonin on HCC cell viability, cell cycle progression and apoptosis were analyzed by utilizing CCK-8 and flow cytometry. RNA-seq was employed to analyze the expression profiles between wogonin-treated and control HCC cells, and the selected RNA-seq transcripts were validated by Reverse Transcription-quantitative realtime Polymerase Chain Reaction (RT-qPCR). Immunofluorescence staining was performed to detect the distribution of YAP/TAZ in the nucleus and cytoplasm in HCC cells. Western blotting and human apoptosis array were performed to examine the expression of the indicated genes. We demonstrated that wogonin induced cell cycle arrest and apoptosis of HCC cell lines SMMC7721 and HCCLM3. RNA-seq analysis showed enrichment in genes associated with cell cycle progression and apoptosis following incubation with wogonin in HCC cells, and the pathways analysis further identified that Hippo signaling pathways highly altered in wogonin-treated cells. Specifically, wogonin increased the phosphorylation of MOB1 and LATS1, promoted translocation of endogenous YAP and TAZ from the nucleus to the cytoplasm, and facilitated phosphorylation of YAP and TAZ. Notably, overexpression of YAP or TAZ partially abrogated the wogonin-mediated HCC cell cycle arrest and apoptosis, and reversed wogonin-mediated suppression of Claspin. Wogonin induced HCC cell cycle arrest and apoptosis probably by activating MOB1-LATS1 signaling to inhibit the activation of YAP and TAZ, and then decrease the expression of Claspin, suggesting that the understanding of the molecular mechanisms underlying wogonin-induced cell cycle arrest and apoptosis may be useful in HCC therapeutics.

TAZ promotes vasculogenic mimicry in gastric cancer through the upregulation of TEAD4.

Vasculogenic mimicry (VM) is a unique blood supply pattern in malignant tumors that is closely associated with metastasis and poor prognosis. The Hippo signaling effector TAZ is upregulated in several cancers, promoting cancer proliferation and metastasis. This study aimed to identify the function of TAZ and its regulatory mechanism in promoting VM in gastric cancer (GC). The expression of TAZ and TEAD4 and their correlations with overall survival and VM-related markers were analyzed in 228 cases of GC. The regulatory mechanism of TAZ and its interaction with TEAD4 in epithelial-mesenchymal transition (EMT) and VM were investigated in vitro and in vivo. TAZ was highly expressed in GC samples and was associated with shorter patient survival time. TAZ expression was positively correlated with TEAD4 and VM in patients with GC. TAZ enhanced the migration and invasion capacity of GC cells through EMT in vitro and upregulated the expression of VM-associated proteins, including VE-cadherin, MMP2, and MMP9, thus promoting VM formation. Overexpression of TAZ accelerated the growth of subcutaneous xenograft and promoted VM formation in vivo. Co-immunoprecipitation assays showed that TAZ can directly bind to TEAD4, and in vitro experiments showed that this binding mediates the function of TAZ in regulating EMT and VM formation in GC. TAZ promotes GC metastasis and VM by upregulating TEAD4 expression. Our findings expand the role of TAZ in VM and provide new theoretical support for the use of antiangiogenic therapy in the treatment of advanced GC.

TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states.

The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiological and pathological states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ is abundantly expressed in pericentral hepatocytes and its expression is markedly reduced by fasting. TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to the GR response element in gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate that hepatic TAZ inhibits GR transactivation of gluconeogenic genes and coordinates gluconeogenesis in response to physiological fasting and feeding.

TAZ inhibits osteoclastogenesis by attenuating TAK1/NF-\u03baB signaling

Osteoporosis is an osteolytic disorder commonly associated with excessive osteoclast formation. Transcriptional coactivator with PDZ-binding motif (TAZ) is a key downstream effector of the Hippo signaling pathway; it was suggested to be involved in the regulation of bone homeostasis. However, the exact role of TAZ in osteoclasts has not yet been established. In this study, we demonstrated that global knockout and osteoclast-specific knockout of TAZ led to a low-bone mass phenotype due to elevated osteoclast formation, which was further evidenced by in vitro osteoclast formation assays. Moreover, the overexpression of TAZ inhibited RANKL-induced osteoclast formation, whereas silencing of TAZ reduced it. Mechanistically, TAZ bound to TGF-activated kinase 1 (TAK1) and reciprocally inhibited NF-κB signaling, suppressing osteoclast differentiation. Collectively, our findings highlight an essential role of TAZ in the regulation of osteoclastogenesis in osteoporosis and its underlying mechanism.

TAZ is required for chondrogenesis and skeletal development

Chondrogenesis is a major contributor to skeletal development and maintenance, as well as bone repair. Transcriptional coactivator with PDZ-binding motif (TAZ) is a key regulator of osteogenesis and adipogenesis, but how TAZ regulates chondrogenesis and skeletal development remains undefined. Here, we found that TAZ expression is gradually increased during chondrogenic differentiation. Deletion of TAZ in chondrocyte lineage impaired articular and growth plate, as well as the bone development in TAZ-deficient mice. Consistently, loss of TAZ impaired fracture healing. Mechanistically, we found that ectopic expression of TAZ markedly promoted chondroprogenitor proliferation, while deletion of TAZ impaired chondrocyte proliferation and differentiation. TAZ associated with Sox5 to regulate the expression and stability of Sox5 and downstream chondrocyte marker genes’ expression. In addition, overexpression of TAZ enhanced Col10a1 expression and promoted chondrocyte maturation, which was blocked by deletion of TAZ. Overall, our findings demonstrated that TAZ is required for skeletal development and joint maintenance that provided new insights into therapeutic strategies for fracture healing, heterotopic ossification, osteoarthritis, and other bone diseases.

Curcumin suppresses the stemness of non-small cell lung cancer cells via promoting the nuclear-cytoplasm translocation of TAZ.

Curcumin has been shown to suppress the progression of lung cancer, however, the underlying mechanisms are largely unknown. Here, we aimed to investigate the effects of curcumin on the stemness of non-small cell lung cancer (NSCLC) cells. We found that curcumin reduced the sphere formation ability at the concentrations without affecting the cell viability of NSCLC cells and normal pulmonary epithelial cells, which is evident by the decrease of sphere size and number. In addition, curcumin decreased ALDH activity and the expression of stemness markers (CD133, EpCAM, Oct4). RNA sequencing analysis revealed that the Hippo pathway was mostly enriched in cells with curcumin treatment. Indeed, the expression of cancer stem cell markers was significantly decreased by curcumin treatment by analyzing the RNA sequencing data. Gene set enrichment analysis (GSEA) showed that curcumin negatively regulated the cancer stem cell function and positively modulated cancer stem cell differentiation ability. Furthermore, curcumin enhanced the cisplatin sensitivity of NSCLC cells. Mechanistically, it was found that curcumin promoted the nuclear-cytoplasm translocation of TAZ, but not YAP, the critical effectors of Hippo pathway. In addition, curcumin destabilzed TAZ protein stability and promoted TAZ protein degradation in lung cancer cells, which is dependent on the proteasome degradation system, not by autophagy lysosome degradation system. Overexpression of TAZ rescued the inhibition of curcumin on the stemness of lung cancer cells. Thus, our results suggest that curcumin can attenuate the stemness of lung cancer cells through promoting TAZ protein degradation and thus activating Hippo pathway.

Antitumor Effects of Paeoniflorin on Hippo Signaling Pathway in Gastric Cancer Cells.

Background Paeoniflorin has been reported to exert antitumor effects on human cancers. However, the role of paeoniflorin in gastric cancer and the underlying molecular mechanism are unelucidated. Therefore, we determined whether paeoniflorin could exhibit anticancer activity in gastric cancer cells. Methods MTT was used to measure the viability of cells after paeoniflorin treatment. FACS was performed to examine cell apoptosis. Wound healing and transwell invasion assays were conducted to examine cell migratory and invasive activities. Western blotting was used to explore the mechanism by which paeoniflorin exerted tumor suppressive effects. Results We found that paeoniflorin suppressed cell growth, enhanced apoptosis, and reduced cell invasion. Notably, we showed that paeoniflorin inhibited the expression of TAZ in gastric cancer cells. The overexpression of TAZ abrogated the antitumor activity of paeoniflorin in gastric cancer cells. In contrast, the downregulation of TAZ promoted the tumor suppressive effects of paeoniflorin treatment. Conclusion Hence, targeting TAZ with paeoniflorin could be a novel approach for the treatment of human gastric cancer.

Thymine DNA glycosylase‐regulated TAZ promotes radioresistance by targeting nonhomologous end joining and tumor progression in esophageal cancer

Radiation resistance is a major cause of esophageal cancer relapse or metastasis. Transcriptional coactivator with PDZ binding domain (TAZ) is a final effector of the Hippo signaling pathway and plays critical roles in several types of cancer, but how it participates in the progression and radiation resistance of esophageal cancer remains unclear. Here, we revealed that TAZ was the strongest prognostic factor among Hippo pathway members. Overexpression of TAZ predicted poor outcome and adverse pathological features. In cell and animal models, TAZ facilitated cell proliferation, motility, and radiation resistance. Additionally, TAZ promoted expression of nonhomologous end joining (NHEJ)‐related genes, which are the main contributors to repair irradiation‐induced DNA breaks and result in radiation resistance. Amplification of the TAZ gene occurred in 2.5%‐3.2% of esophageal cancers. In addition, the CpG islands of the TAZ gene were demethylated in esophageal cancer under thymine DNA glycosylase (TDG) regulation. Knockdown of TDG inhibited cell growth, motility, and radiation resistance, which were overridden by TAZ overexpression. Collectively, these findings suggest that the TDG/TAZ/NHEJ axis is a critical player in esophageal cancer progression and radiation resistance, as well as a potential target for radiotherapy.

MiR-140 inhibits osteogenic differentiation of human periodontal ligament fibroblasts through ras homolog gene family, member A -transcriptional co-activator with PDZ-binding motif pathway.

Osteogenesis induced by mechanical stretch is the main factor affecting the orthodontic treatment. Due to the masticatory force transmitted by tooth, human periodontal ligament fibroblasts (hPDLFs) could enhance osteogenic differentiation, and remolding of periodontal. Therefore, in-depth study of hPDLFs osteogenic differentiation and its regulatory mechanism is helpful in the understanding of periodontal remolding promoted by orthodontic force. In the present study, 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide showed that miR-140 inhibited the viability of hPDLFs cells. Moreover, we provided evidence that miR-140 inhibited alkaline phosphatase (ALP) activity, Alizarin Red S (ARS) activity and the mRNA expression of osteogenesis associated genes, including ALP, runt-related transcription factor 2, collagen 1, and osteocalcin. Besides, double-luciferase reporter result demonstrated that Ras homolog gene family, member A (RhoA) was a downstream target gene of miR-140, and by inhibiting RhoA-transcriptional co-activator with PDZ-binding motif (TAZ) signaling pathway, miR-140 suppressed the osteogenesis differentiation of hPDLFs. Furthermore, overexpression of RhoA or TAZ promoted ALP activity, ARS activity and osteogenesis associated genes expression, which was inhibited by miR-140 mimics. Our findings not only provided a possible mechanism of hPDLFs osteogenic differentiation but also proposed the clinical application of miR-140 inhibitor to target RhoA-TAZ for orthodontic treatment.

Abstract B33: Genome-scale CRISPR/Cas9 screening identifies Hippo pathway as key determinant for susceptibility to BET inhibitors in lung cancer

Abstract Lung cancer is the main cause of cancer-related mortality worldwide. Despite the availability of different therapeutic options, including chemotherapy, target therapy, and immunotherapy, prognosis for lung cancer patients remains poor. Among innovative therapeutic approaches, inhibitors of the bromodomain and extraterminal domain containing proteins (BETi) have proven efficacy in preclinical settings and are currently in clinical trials for hematologic and solid tumors, including lung cancer. BETi downregulate key oncogenes to which cancer cells are addicted, causing a decrease in proliferation and an increase in apoptosis and differentiation. However, biomarkers that can help to select patients for this treatment are still lacking. To discover the mechanisms responsible of susceptibility and/or resistance to BETi, we performed a genome-scale knockout screening using the CRISPR/Cas9 technology in lung cancer cells. Through this approach, we identified three genes belonging to Hippo pathway, LATS2, TAOK1, and NF2, as mediators of susceptibility to BETi. Hippo pathway is an oncosuppressor pathway that converges on the phosphorylation of YAP1 and TAZ. YAP1 and TAZ are two transcriptional coactivators that interact with TEAD family proteins in nucleus for the activation of pro-oncogenic transcriptional programs. Phosphorylated YAP1 and TAZ are excluded from nucleus, degraded, and unable to enhance the expression of their target genes. We showed that LATS2, TAOK1, and NF2 support susceptibility to BETi, restraining TAZ nuclear localization and activity. We observed that TAZ knockout increases sensitivity whereas TAZ overexpression supports resistance to BETi. Furthermore, we showed that TAZ, YAP1, and TEAD are direct targets of BRD4 and their expression is downregulated by BETi treatment in a large panel of cancer cell lines. Noticeably, molecular alterations in YAP1, TAZ or in the Hippo genes LATS2, TAOK1, and NF2 are present in 19% of all non-small cell lung cancer patients, and overexpression or amplification of TAZ correlates with a worse outcome in lung adenocarcinoma patients. Our data demonstrate that Hippo pathway genes are required for susceptibility to BETi by restraining TAZ activity as transcriptional coactivator, and suggest that this mechanism can be exploited to detect and overcome drug resistance in lung cancer. BETi-mediated downregulation of the YAP1/TAZ/TEAD transcriptional activity provides a rationale for using these drugs to counteract the activity of these pro-oncogenic transcription factors. Citation Format: Giulia Gobbi, Benedetta Donati, Italo Faria Do Valle, Francesca Reggiani, Federica Torricelli, Daniel Remondini, Gastone Castellani, Davide Carlo Ambrosetti, Alessia Ciarrocchi, Valentina Sancisi. Genome-scale CRISPR/Cas9 screening identifies Hippo pathway as key determinant for susceptibility to BET inhibitors in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B33.

Cryptotanshinone attenuates the stemness of non-small cell lung cancer cells via promoting TAZ translocation from nuclear to cytoplasm

BackgroundCancer stem cells (CSCs) are regarded as the root of tumor progression, thus representing an anti-cancer therapy through targeting this cell sub-population.MethodsNon-small cell lung cancer (NSCLC) CSCs were enriched by non-adherent spheroid formation analysis. Lentivirus infection was used to stably change gene expression. Cell cycle, EdU incorporation, cell apoptosis, cell viability, ALDH1 activity, spheroid formation and in vivo tumor initiation assays were performed to detect the effects of Cryptotanshinone (CT), a traditional Chinese herb medicine, on the stemness of NSCLC cells. RNA-sequencing combined qRT-PCR and western blot analysis were constructed to explore the underlying mechanism contributing to CT-mediated effects.ResultsCT could attenuate the stemness of NSCLC CSCs, as evident by the reduced spheroid formation ability, stemness marker expression and ALDH1 activity. Additionally, CT provoked NSCLC CSCs entry into the cell cycle. RNA-sequencing analysis showed that Hippo signaling pathway was highly enriched in NSCLC CSCs with CT treatment. Further experiments disclosed that CT decreased TAZ (a regulatory master of Hippo pathway) expression via promoting its nuclear-cytoplasm translocation in NSCLC CSCs. Also, overexpression of TAZ partially saved the attenuation of CT on the stemness of NSCLC CSCs. Notably, CT enhanced the sensitivity of tyrosine kinase inhibitor (TKI) and chemotherapy in NSCLC CSCs.ConclusionsThis work reveals that CT attenuates NSCLC CSC stemness, implying the possibility of CT as an adjuvant therapy for NSCLC.

Knockdown of microRNA-584 promotes dental pulp stem cells proliferation by targeting TAZ

ABSTRACT Proliferation of dental pulp stem cells (DPSCs) is crucial in tooth development and damage repairing, also includes its therapy application for tissue engineering. MicroRNAs (miRNAs) are key players in biological processes of DPSCs, and transcriptional co-activator with PDZ-binding motif (TAZ) also plays important roles in cell proliferation and differentiation, however, the roles of miR-584 and TAZ in DPSCs are not known. We found up-regulated miR-584 expression and down-regulated TAZ expression levels in aging dental pulp tissue compare to those in young dental pulp tissue. In proliferating DPSCs we demonstrated the decreased miR-584 expression and increased TAZ expression. miR-584 mimics suppressed DPSCs proliferation and migration, and significantly reduced TAZ production, whereas miR-584 inhibition exerted the converse effects. Knocking down of the TAZ in DPSCs had a similar effect as overexpression of miR-584. Furthermore, luciferase reporter assay demonstrated that miR-584 could directly bind to the TAZ mRNA 3ʹUTR to repress its translation. Overexpression of TAZ can partly rescue miR-584 mimic-mediated the inhibition of proliferation. Additionally, miR-584 inhibited cell proliferation and downregulated expression of cell cycle proteins by AKT signaling pathway. Together, we identified that miR-584 may be a key regulator in the proliferation of DPSCs by regulating TAZ expression via AKT signaling pathway. It would be a promising biomarker and therapeutic target for pulp disease.

Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence.

Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.

Overexpression of transcriptional co-activator with PDZ-binding motif promotes epithelial mesenchymal transformation of ovarian cancer cells by upregulating Smad3 and Snail1

This study is intended to explore the effect of transcriptional coactivator with PDZ binding motif (TAZ) expression in ovarian cancer cells as well as investigate the expression of signal proteins Smad3 and Snail1. Ovarian cancer cells (SKOV-3) were divided into two groups: control and TAZ overexpression. The overexpression of TAZ in SKOV-3 cells was determined by immunofluorescence, western blot, and qRT-PCR. The proliferation, invasiveness, and expression of epithelial mesenchymal transformation (EMT)-associated proteins were detected, and the expression of Smad3 and Snail1 proteins was determined by qRT-PCR and western blot, respectively. Small interfering RNA (siRNA) targeting TAZ were synthesized and used to transfect SKOV-3. Cell migration and invasion were observed via a wound healing assay and a transwell assay, respectively. The expressions of representative genes involved in proliferation and migration, EMT-associated proteins and Smad3 and Snail1 proteins were also detected by western blot assays. The results of qRT-PCR, immunofluorescence, and western blot showed that, compared with the control group, the expressions of Smad3 and Snail1 protein were upregulated, and the expression of EMT-related genes-including Actin, N-cadherin, and Vimentin protein-was downregulated in the TAZ overexpression group. After TAZ mRNA was suppressed, the migration and invasion ability of the TAZ siRNA group was weaker than that of the control group. In addition, the expression level of Smad3 and Snail1 decreased when TAZ was silenced, while the expression of EMT-related genes increased. Therefore, TAZ in ovarian cancer cells can promote growth, migration, and invasiveness of cancer cells by regulating genes related to proliferation, migration, and invasion.

TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC

AbstractMultiple myeloma (MM) is an incurable blood cancer that is often characterized by amplification and overexpression of the MYC oncogene. Despite efforts, direct targeting of MYC is not yet possible; therefore, alternative strategies to inhibit MYC activity are necessary. TAZ is a transcriptional coactivator downstream of the Hippo-signaling pathway that functions as an oncogene in many solid tumors. However, its role in hematological malignancies is largely unexplored. Here, we show that, in contrast to solid tumors, expression of TAZ is lower in hematological malignancies, and that high expression of TAZ correlates with better patient outcomes. We further show that TAZ is hypermethylated in MM patient samples and in a panel of MM cell lines. Genetic overexpression of TAZ or pharmacological upregulation of TAZ by treatment with the demethylating agent decitabine induces apoptosis. Importantly, TAZ-induced apoptosis is independent of canonical Hippo components LATS1 or the TEA-domain family of transcription factors. Instead, RNA-sequencing analysis revealed that overexpression of TAZ represses a MYC transcriptional program and we show that increased TAZ expression correlates with decreased MYC expression in both cell-line models and patient samples. Furthermore, promoter derepression of TAZ expression sensitizes MM cell lines through a reciprocal reduction in MYC expression using additional therapeutics such as bortezomib, trichostatin A, and panobinostat. Our findings uncover an unexpected role for TAZ in MM tumorigenesis and provide a compelling rationale for exploring the therapeutic potential of upregulating TAZ expression to restore sensitivity to specific therapeutics in MM.