Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo.

Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM.

Substrate stiffness-dependent activation of Hippo pathway in cancer associated fibroblasts.

The tumor microenvironment (TME) comprises a heterogenous cell population within a complex three-dimensional (3D) extracellular matrix (ECM). Stromal cells within this TME are altered by signaling cues from cancer cells to support uncontrolled tumor growth and invasion events. Moreover, the ECM also plays a fundamental role in tumor development through pathological remodeling, stiffening and interaction with TME cells. In healthy tissues, Hippo signaling pathway actively contributes to tissue growth, cell proliferation and apoptosis. However, in cancer, the Hippo signaling pathway is highly dysregulated, leading to nuclear translocation of the YAP/TAZ complex, which directly contributes to uncontrolled cell proliferation and tissue growth, and ECM remodeling and stiffening processes. Here, we compare the effect of increasing cell culture substrate stiffness, derived from tumor progression, upon the dysregulation of the Hippo signaling pathway in colorectal cancer-associated fibroblasts (CAFs) and normal colorectal fibroblasts (NFs). We correlate the dysregulation of Hippo pathway with the magnitude of the traction forces exerted by healthy and malignant stromal cells. We found that ECM stiffening is crucial in Hippo pathway dysregulation in CAFs, but not in normal fibroblasts.

[Research progress on the regulatory mechanism of Hippo signaling pathway in pulmonary fibrosis].

Pulmonary fibrosis is a difficult to treat fibrotic disease with multiple triggering factors and complex pathogenesis. It is characterized by diffuse inflammatory damage, tissue structure destruction, and persistent fibrosis, resulting in irreversible damage to lung function. The Hippo signaling pathway is involved in regulating various biological processes such as cell proliferation, differentiation, migration, apoptosis, and is closely related to the occurrence of pulmonary fibrosis. In order to further explore the mechanism of pulmonary fibrosis, this paper comprehensively analyzes the Hippo signaling pathway and its cellular and pathological imbalance related to pulmonary fibrosis, revealing the influence of Hippo signaling pathway in pulmonary fibrosis and its possible mechanism of action, which is expected to provide new targets and strategies for the prevention and treatment of pulmonary fibrosis.

Notch-Driven Cholangiocarcinogenesis Involves the Hippo Pathway Effector TAZ via METTL3-m6A-YTHDF1.

BACKGROUND AND AIMS: Notch and TAZ are implicated in cholangiocarcinogenesis, but whether and how these oncogenic molecules interact remain unknown. METHODS: The development of CCA was induced by hydrodynamic tail vein (HDTV) injection of oncogenes (NICD/AKT) to the FVB/NJ mice. CCA xenograft was developed by inoculation of human CCA cells into the livers of SCID mice. Tissues and cells were analyzed using qRT-PCR, Western blotting analyses, Immunohistochemistry, ChIP-qPCR and WST-1 cell proliferation Assay. RESULTS: Our experimental findings show that TAZ is indispensable in NICD-driven cholangiocarcinogenesis. Notch activation induces the expression of METTL3 (Methyltransferase like-3) which catalyzes N6-methyladenosine (m6A) modification of TAZ mRNA and that this mechanism plays a central role in the crosstalk between Notch and TAZ in CCA cells. Mechanistically, Notch regulates the expression of METTL3 through the binding of NICD to its downstream transcription factor CSL in the promoter region of METTL3. METTL3 in turn mediates m6A modification of TAZ mRNA which is recognized by the m6A reader YTHDF1 to enhance TAZ protein translation. We observed that inhibition of Notch signaling decreased the protein levels of both MELLT3 and TAZ. Depletion of METTL3 by shRNAs or by the next generation GapmeR antisense oligonucleotides (ASOs) decreased the level of TAZ protein and inhibited the growth of human CCA cells in vitro and in mice. CONCLUSION: This study describes a novel Notch-METTL3-TAZ signaling cascade which is important in CCA development and progression. Our experimental results provide new insight into how the Notch pathway cooperates with TAZ signaling in CCA, and the findings may have important therapeutic implications.

Role of the Hippo-YAP/TAZ Pathway in Epithelioid Hemangioendothelioma and its Potential as a Therapeutic Target.

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor arising from vascular endothelial cells. This study delves into the molecular mechanisms underlying EHE, with a specific focus on the Hippo-YAP/TAZ pathway. EHE is characterized molecularly by transcriptional co-activator with a PDZ-motif (TAZ)-calmodulin binding transcription activator 1 (CAMTA1) or Yes-associated protein (YAP)-transcription factor E3 (TFE3) fusions. YAP/TAZ, a transcription co-activator, binds to transcription factors and regulates gene expression. The YAP/TAZ and its upstream Hippo pathway are involved in cell proliferation and cell contact inhibition, regulating organ size and carcinogenesis. In addition to oncogenic effects, dysfunction or gene duplication of the Hippo pathway results in a poor prognosis due to epithelial-mesenchymal transformation of epithelial cells, stem cell transformation, and increased drug resistance. Notably, the TAZ-CAMTA1 fusion is specific to EHE, and genetic alterations in the Hippo pathway other than this fusion gene are absent in EHE. The TAZ-CAMTA1 fusion is a promising therapeutic target. This review summarizes recent advances in EHE, focusing on the role of the Hippo-YAP/TAZ pathway in EHE and its potential as a therapeutic target for drug development.

YAP/TAZ Signaling in the Pathobiology of Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a severe, irreversible lung disease characterized by progressive scarring, with idiopathic pulmonary fibrosis (IPF) being the most prevalent form. IPF's pathogenesis involves repetitive lung epithelial injury leading to fibroblast activation and excessive extracellular matrix (ECM) deposition. The prognosis for IPF is poor, with limited therapeutic options like nintedanib and pirfenidone offering only modest benefits. Emerging research highlights the dysregulation of the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway as a critical factor in PF. YAP and TAZ, components of the Hippo pathway, play significant roles in cell proliferation, differentiation, and fibrosis by modulating gene expression through interactions with TEA domain (TEAD) transcription factors. The aberrant activation of YAP/TAZ in lung tissue promotes fibroblast activation and ECM accumulation. Targeting the YAP/TAZ pathway offers a promising therapeutic avenue. Preclinical studies have identified potential treatments, such as trigonelline, dopamine receptor D1 (DRD1) agonists, and statins, which inhibit YAP/TAZ activity and demonstrate antifibrotic effects. These findings underscore the importance of YAP/TAZ in PF pathogenesis and the potential of novel therapies aimed at this pathway, suggesting a new direction for improving IPF treatment outcomes. Further research is needed to validate these approaches and translate them into clinical practice.

Wnt/ß-Catenin Signaling Regulates Yap/Taz Activity during Embryonic Development in Zebrafish.

Hippo-YAP/TAZ and Wnt/ß-catenin signaling pathways, by controlling proliferation, migration, cell fate, stemness, and apoptosis, are crucial regulators of development and tissue homeostasis. We employed zebrafish embryos as a model system to elucidate in living reporter organisms the crosstalk between the two signaling pathways. Co-expression analysis between the Wnt/ß-catenin Tg(7xTCF-Xla.Siam:GFP)ia4 and the Hippo-Yap/Taz Tg(Hsa.CTGF:nlsmCherry)ia49 zebrafish reporter lines revealed shared spatiotemporal expression profiles. These patterns were particularly evident in key developmental regions such as the midbrain-hindbrain boundary (MHB), epidermis, muscles, neural tube, notochord, floorplate, and otic vesicle. To investigate the relationship between the Wnt/ß-catenin pathway and Hippo-Yap/Taz signaling in vivo, we conducted a series of experiments employing both pharmacological and genetic strategies. Modulation of the Wnt/ß-catenin pathway with IWR-1, XAV939, or BIO resulted in a significant regulation of the Yap/Taz reporter signal, highlighting a clear correlation between ß-catenin and Yap/Taz activities. Furthermore, genetic perturbation of the Wnt/ß-catenin pathway, by APC inhibition or DKK1 upregulation, elicited evident and robust alteration of Yap/Taz activity. These findings revealed the intricate regulatory mechanisms underlying the crosstalk between the Wnt/ß-catenin and Hippo-Yap/Taz signaling, shedding light on their roles in orchestrating developmental processes in vivo.

The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives.

Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play a role in numerous malignant phenotypes, including hyperproliferation, invasion, and metastasis. These phenotypes correlate with activity of the Hippo pathway oncoprotein, Yes-associated protein-1 (YAP1), and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ). YAP1/TAZ are normally involved in organ growth, under the regulation of various kinases and upon phosphorylation, are retained in the cytoplasm by chaperone proteins, leading to their proteasomal degradation. In CAFs and tumor cells, however, a lack of YAP1 phosphorylation results in its translocation to the nucleus, binding to TEAD transcription factors, and activation of mitogenic pathways. In this review we summarize the literature discussing the central role of YAP1 in CAF activation, the upstream cues that promote YAP1-mediated CAF activation and extracellular matrix remodeling, and how CAFs mediate tumor-stroma crosstalk to support progression, invasion and metastasis in various cancer models. We further highlight YAP1+CAFs functions in modulating an immunosuppressive tumor microenvironment and propose evaluation of several YAP1 targets regarding their role in regulating intra-tumoral immune landscapes. Finally, we propose that co-administration of YAP1- targeted therapies with immune checkpoint inhibitors can improve therapeutic outcomes in patients with advanced tumors.

Poison Turned Panacea: Arsenic Trioxide Loaded Hydrogel for Inhibiting Scar Formation in Wound Healing.

Without intervention, the natural wound healing process can often result in scarring, which can have detrimental effects on both the physical and mental well-being of patients. Therefore, it is crucial to develop biomaterials that can promote healing without scarring. Regulating the Yes-associated protein-1/PDZ-binding motif (YAP/TAZ) signaling pathway is possible to reduce excessive fibrosis of fibroblasts and proliferation of vascular endothelial cells, ultimately impacting scar formation. Arsenic trioxide (ATO), an ancient drug with medicinal and toxic properties, has shown promise in regulating this pathway. An ATO-loaded hydrogel dressing (ATO@CS/SA) was created to facilitate scarless wound healing, utilizing chitosan (CS) and sodium alginate (SA) to prevent direct contact of ATO with the wound tissue and minimize potential side effects. In vitro studies demonstrated that low concentrations of ATO did not impact cell viability and even promoted proliferation and migration. Co-culturing the hydrogel with fibroblasts and vascular endothelial cells led to decreased expression levels of YAP and TAZ. Animal studies over a 90-day period revealed significant inhibition of scar formation with this system. Histological experiments further confirmed that the decreased expression of YAP and TAZ was responsible for this outcome. In conclusion, when administered at the appropriate dose, ATO can be repurposed from a traditional poison to a therapeutic agent, effectively suppressing excessive cell fibrosis and blood vessel proliferation and offering a novel approach to scar-free treatment.

Dual function of PHF16 in reinstating homeostasis of murine intestinal epithelium after crypt regeneration.

Intestinal stem cells (ISCs) are highly vulnerable to damage, being in a constant state of proliferation. Reserve stem cells repair the intestinal epithelium following damage-induced ablation of ISCs. Here, we report that the epigenetic regulator plant homology domain (PHD) finger protein 16 (PHF16) restores homeostasis of the intestinal epithelium after initial damage-induced repair. In Phf16-/Y mice, revival stem cells (revSCs) showed defects in exiting the regenerative state, and intestinal crypt regeneration failed even though revSCs were still induced in response to tissue damage, as observed by single-cell RNA sequencing (scRNA-seq). Analysis of Phf16-/Y intestinal organoids by RNA sequencing (RNA-seq) and ATAC sequencing identified that PHF16 restores homeostasis of the intestinal epithelium by inducing retinoic acid receptor (RAR)/retinoic X receptor (RXR) target genes through HBO1-mediated histone H3K14 acetylation, while at the same time counteracting YAP/TAZ activity by ubiquitination of CDC73. Together, our findings demonstrate the importance of timely suppression of regenerative activity by PHF16 for the restoration of gut homeostasis after acute tissue injury.

ß-1,4-Galactosyltransferase 1 protects against cerebral ischemia injury in mice by suppressing ferroptosis via the TAZ/Nrf2/HO-1 signaling pathway.

BACKGROUND: Ischemic stroke leads a primary cause of mortality in human diseases, with a high disability rate worldwide. This study aims to investigate the function of ß-1,4-galactosyltransferase 1 (B4galt1) in mouse brain ischemia/reperfusion (I/R) injury. METHODS: Recombinant human B4galt1 (rh-B4galt1) was intranasally administered to the mice model of middle cerebral artery occlusion (MCAO)/reperfusion. In this study, the impact of rh-B4galt1 on cerebral injury assessed using multiple methods, including the neurological disability status scale, 2,3,5-triphenyltetrazolium chloride (TTC), Nissl and TUNEL staining. This study utilized laser speckle Doppler flowmeter to monitor the cerebral blood flow. Western blotting was performed to assess the protein expression levels, and fluorescence-labeled dihydroethidium method was performed to determine the superoxide anion generation. Assay kits were used for the measurement of iron, malondialdehyde (MDA) and glutathione (GSH) levels. RESULTS: We demonstrated that rh-B4galt1 markedly improved neurological function, reduced cerebral infarct volume and preserved the completeness of blood-brain barrier (BBB) for preventing damage. These findings further illustrated that rh-B4galt1 alleviated oxidative stress, lipid peroxidation, as well as iron deposition induced by I/R. The vital role of ferroptosis was proved in brain injury. Furthermore, the rh-B4galt1 could increase the levels of TAZ, Nrf2 and HO-1 after I/R. And TAZ-siRNA and ML385 reversed the neuroprotective effects of rh-B4galt1. CONCLUSIONS: The results indicated that rh-B4galt1 implements neuroprotective effects by modulating ferroptosis, primarily via upregulating TAZ/Nrf2/HO-1 pathway. Thus, B4galt1 could be seen as a promising novel objective for ischemic stroke therapy.

Identifying adeno-associated virus (AAV) vectors that efficiently target high grade glioma cells, for in vitro monitoring of temporal cell responses.

To improve the translation of preclinical cancer research data to successful clinical effect, there is an increasing focus on the use of primary patient-derived cancer cells with limited growth in culture to reduce genetic and phenotype drift. However, these primary lines are less amenable to standardly used methods of exogenous DNA introduction. Adeno-associated viral (AAV) vectors display tropism for a wide range of human tissues, avidly infect primary cells and have a good safety profile. In the present study, we therefore used a next-generation sequencing (NGS) barcoded AAV screening method to assess transduction capability of a panel of 36 AAVs in primary cell lines representing high-grade glioma (HGG) brain tumours including glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG). As proof of principle, we created a reporter construct to analyse activity of the transcriptional co-activators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Transcriptional activation was monitored by promoter-driven expression of the Timer fluorescent tag, a protein that fluoresces green immediately after transcription and transitions to red fluorescence over time. As expected, attempts to express the reporter in primary HGG cells from plasmid expression vectors were unsuccessful. Using the top candidate from the AAV screen, we demonstrate successful AAV-mediated transduction of HGG cells with the YAP/TAZ dynamic activity reporter. In summary, the NGS-screening approach facilitated screening of many potential AAVs, identifying vectors that can be used to study the biology of primary HGG cells.

YAP/TAZ as mechanobiological signaling pathway in cardiovascular physiological regulation and pathogenesis.

Cardiovascular diseases (CVDs) persistently rank as a leading cause of premature death and illness worldwide. The Hippo signaling pathway, known for its highly conserved nature and integral role in regulating organ size, tissue homeostasis, and stem cell function, has been identified as a critical factor in the pathogenesis of CVDs. Recent findings underscore the significance of the Yes-associated protein (YAP) and the Transcriptional Coactivator with PDZ-binding motif (TAZ), collectively referred to as YAP/TAZ. These proteins play pivotal roles as downstream components of the Hippo pathway, in the regulation of cardiovascular development and homeostasis. YAP/TAZ can regulate various cellular processes such as cell proliferation, migration, differentiation, and apoptosis through their interactions with transcription factors, particularly those within the transcriptional enhancer associate domain (TEAD) family. The aim of this review is to provide a comprehensive overview of the current understanding of YAP/TAZ signaling in cardiovascular physiology and pathogenesis. We analyze the regulatory mechanisms of YAP/TAZ activation, explore their downstream effectors, and examine their association across numerous cardiovascular disorders, including myocardial hypertrophy, myocardial infarction, pulmonary hypertension, myocardial ischemia-reperfusion injury, atherosclerosis, angiogenesis, restenosis, and cardiac fibrosis. Furthermore, we investigate the potential therapeutic implications of targeting the YAP/TAZ pathway for the treatment of CVDs. Through this comprehensive review, our aim is to elucidate the current understanding of YAP/TAZ signaling in cardiovascular biology and underscore its potential implications for the diagnosis and therapeutic intervention of CVDs.

Regulation of Tumor Microenvironment through YAP/TAZ under Tumor Hypoxia.

In solid tumors such as hepatocellular carcinoma (HCC), hypoxia is one of the important mechanisms of cancer development that closely influences cancer development, survival, and metastasis. The development of treatments for cancer was temporarily revolutionized by immunotherapy but continues to be constrained by limited response rates and the resistance and high costs required for the development of new and innovative strategies. In particular, solid tumors, including HCC, a multi-vascular tumor type, are sensitive to hypoxia and generate many blood vessels for metastasis and development, making it difficult to treat HCC, not only with immunotherapy but also with drugs targeting blood vessels. Therefore, in order to develop a treatment strategy for hypoxic tumors, various mechanisms must be explored and analyzed to treat these impregnable solid tumors. To date, tumor growth mechanisms linked to hypoxia are known to be complex and coexist with various signal pathways, but recently, mechanisms related to the Hippo signal pathway are emerging. Interestingly, Hippo YAP/TAZ, which appear during early tumor and normal tumor growth, and YAP/TAZ, which appear during hypoxia, help tumor growth and proliferation in different directions. Peculiarly, YAP/TAZ, which have different phosphorylation directions in the hypoxic environment of tumors, are involved in cancer proliferation and metastasis in various carcinomas, including HCC. Analyzing the mechanisms that regulate the function and expression of YAP in addition to HIF in the complex hypoxic environment of tumors may lead to a variety of anti-cancer strategies and combining HIF and YAP/TAZ may develop the potential to change the landscape of cancer treatment.

Wedelolactone Attenuates Liver Fibrosis and Hepatic Stellate Cell Activation by Suppressing the Hippo Pathway.

Liver fibrosis is a commonly observed pathological phenomenon that occurs during the progression of various types of chronic liver diseases. The Hippo pathway is closely associated with the pathogenesis of liver fibrosis. Previous studies have shown that wedelolactone (WED) has a significant antihepatic fibrosis effect, whereas the target and mechanism underlying WED remain elusive. In this study, we found that WED significantly alleviated liver fibrosis and injury by inhibiting the expression of Yes-associated protein (YAP) and tafazzin (TAZ). In an in vitro model, WED suppressed the activation of hepatic stellate cells (HSCs) induced by transforming growth factor (TGF-ß1), as well as the mRNA and protein expression of α-smooth muscle actin (α-SMA), YAP, and TAZ. The allosteric regulation of YAP by WED was confirmed using MD and cellular thermal shift assay. Moreover, specific knockdown or inhibition of YAP did not enhance the suppressive effect of WED on HSC activation or protein expression associated with fibrosis. These findings demonstrated that the administration of WED effectively alleviated liver fibrosis by suppressing the Hippo/YAP/TAZ pathways. In addition, YAP activity may be regulated by WED via allosteric regulation.

A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells.

The activation of yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) has been implicated in both regeneration and tumorigenesis, thus representing a double-edged sword in tissue homeostasis. However, how the activity of YAP1/TAZ is regulated or what leads to its dysregulation in these processes remains unknown. To explore the upstream stimuli modulating the cellular activity of YAP1/TAZ, we developed a highly sensitive YAP1/TAZ/TEAD-responsive DNA element (YRE) and incorporated it into a lentivirus-based reporter cell system to allow for sensitive and specific monitoring of the endogenous activity of YAP1/TAZ in terms of luciferase activity in vitro and Venus fluorescence in vivo. Furthermore, by replacing YRE with TCF- and NF-κB-binding DNA elements, we demonstrated the applicability of this reporter system to other pathways such as Wnt/ß-catenin/TCF- and IL-1ß/NF-κB-mediated signaling, respectively. The practicality of this system was evaluated by performing cell-based reporter screening of a chemical compound library consisting of 364 known inhibitors, using reporter-introduced cells capable of quantifying YAP1/TAZ- and ß-catenin-mediated transcription activities, which led to the identification of multiple inhibitors, including previously known as well as novel modulators of these signaling pathways. We further confirmed that novel YAP1/TAZ modulators, such as potassium ionophores, Janus kinase inhibitors, platelet-derived growth factor receptor inhibitors, and genotoxic stress inducers, alter the protein level or phosphorylation of endogenous YAP1/TAZ and the expression of their target genes. Thus, this reporter system provides a powerful tool to monitor endogenous signaling activities of interest (even in living cells) and search for modulators in various cellular contexts.

Hippo pathway effectors YAP, TAZ and TEAD are associated with EMT master regulators ZEB, Snail and with aggressive phenotype in phyllodes breast tumors.

BACKGROUND: Phyllodes tumors (PTs) of the breast are uncommon fibroepithelial neoplasms that tend to recur locally and may have metastatic potential. Their pathogenesis is poorly understood. Hippo signaling pathway plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. Hippo signaling dysfunction has been implicated in cancer. Recent evidence suggests that there is cross-talk between the Hippo signaling key proteins YAP/TAZ and the epithelial-mesenchymal transition (EMT) master regulators Snail and ZEB. In this study we aimed to investigate the expression of Hippo signaling pathway components and EMT regulators in PTs, in relation to tumor grade. METHODS: Expression of Hippo signaling effector proteins YAP, TAZ and their DNA binding partner TEAD was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 86 human phyllodes breast tumors (45 benign, 21 borderline, 20 malignant), in comparison with tumor grade and with the expression of EMT-related transcription factors ZEB and Snail. RESULTS: Nuclear immunopositivity for YAP, TAZ and TEAD was detected in both stromal and epithelial cells in PTs and was significantly higher in high grade tumors. Interestingly, there was a significant correlation between the expression of YAP, TAZ, TEAD and the expression of ZEB and SNAIL. CONCLUSIONS: Our results originally implicate Hippo signaling pathway in PTs pathogenesis and suggest that an interaction between Hippo signaling key components and EMT regulators may promote the malignant features of PTs.

Emerging Role of Hippo-YAP (Yes-Associated Protein)/TAZ (Transcriptional Coactivator with PDZ-Binding Motif) Pathway Dysregulation in Renal Cell Carcinoma Progression.

Although Hippo-YAP/TAZ pathway involvement has been extensively studied in the development of certain cancers, the involvement of this cascade in kidney cancer progression is not well-established and, therefore, will be the focus of this review. Renal cell carcinoma (RCC), the most prevalent kidney tumor subtype, has a poor prognosis and a high mortality rate. Core Hippo signaling inactivation (e.g., LATS kinases) leads to the nuclear translocation of YAP/TAZ where they bind to co-transcriptional factors such as TEAD promoting transcription of genes which initiates various fibrotic and neoplastic diseases. Loss of expression of LATS1/2 kinase and activation of YAP/TAZ correlates with poor survival in RCC patients. Renal-specific ablation of LATS1 in mice leads to the spontaneous development of several subtypes of RCC in a YAP/TAZ-dependent manner. Genetic and pharmacological inactivation of YAP/TAZ reverses the oncogenic potential in LATS1-deficient mice, highlighting the therapeutic benefit of network targeting in RCC. Here, we explore the unique upstream controls and downstream consequences of the Hippo-YAP/TAZ pathway deregulation in renal cancer. This review critically evaluates the current literature on the role of the Hippo pathway in RCC progression and highlights the recent scientific evidence designating YAP/TAZ as novel therapeutic targets against kidney cancer.