LATS1/2 loss promote tumor immune evasion in endometrial cancer through downregulating MHC-I expression.

BACKGROUND: LATS1/2 are frequently mutated and down-regulated in endometrial cancer (EC), but the contributions of LATS1/2 in EC progression remains unclear. Impaired antigen presentation due to mutations or downregulation of the major histocompatibility complex class I (MHC-I) has been implicated in tumor immune evasion. Herein, we elucidate the oncogenic role that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I. METHODS: The mutation and expression as well as the clinical significance of LATS1/2 in EC was assessed in the TCGA cohort and our sample cohort. CRISPR-Cas9 was used to construct knockout cell lines of LATS1/2 in EC. Differentially expressed genes were analyzed by RNA-seq. The interaction between LATS1/2 and STAT1 was verified using co-immunoprecipitation and GST pull-down assays. Mass spectrometry, in vitro kinase assays, ChIP-qPCR, flow cytometry, immunohistochemistry, immunofluorescence and confocal microscopy were performed to investigate the regulation of LATS1/2 on MHC-I through interaction with and phosphorylate STAT1. The killing effect of activated PBMCs on EC cells were used to monitor anti-tumor activity. RESULTS: Here, we demonstrate that LATS1/2 are frequently mutated and down-regulated in EC. Moreover, LATS1/2 loss was found to be associated with a significant down-regulation of MHC-I, independently of the Hippo-YAP pathway. Instead, LATS1/2 were found to directly interact with and phosphorylate STAT1 at Ser727, a crucial transcription factor for MHC-I upregulation in response to interferon-gamma (IFN-γ) signaling, to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, the loss of LATS1/2 was observed to confer increased resistance of EC cells to immune cell-mediated killing and this resistance could be reversed by over-expression of MHC-I. CONCLUSION: Our findings indicate that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I, leading to the suppression of infiltrating activated CD8 + T cells and highlight the importance of LATS1/2 in IFN-γ signaling-mediated tumor immune response, suggesting that LATS1/2 is a promising target for immune checkpoint blockade therapy in EC.

The TGFß→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1.

The Hippo kinase cascade functions as a central hub that relays input from the "outside world" of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor ß (TGFß)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFß-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFß signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFß-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFß signals and the Hippo pathway (TGFß→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.

Using a Modified Proximity Ligation Protocol to Study the Interaction Between Chaperones and Associated Proteins.

Molecular chaperones can interact with multiple proteins to form large networks. Understanding these interactions may shed light on the complexity of the chaperone functions. Here we developed a protocol for a modified proximity ligation-based methodology (PLA) for the detection of protein-protein interactions in order to understand how the Hsp70-Bag3 complex interacts with components of the Hippo signaling pathway. These experiments helped to elucidate the mechanisms of transmission of the proteotoxic stress signal to the Hippo pathway. The modified PLA technology has many advantages compared to co-immunoprecipitation protocols. It has higher sensitivity, is quantitative, and can be done in a 96-well format.

Low MST1/2 and negative LATS1/2 expressions are associated with poor prognosis of colorectal cancers.

Mammalian STe20-like protein kinase 1/2 (MST1/2) and large tumor suppressor homolog 1/2 (LATS1/2) are the core components of the tumor-suppressive Hippo pathway. Dysregulation of this pathway is associated with the progression and metastasis of various cancers. However, MST1/2 and LATS1/2 expressions have not been systematically evaluated in colorectal cancers. We evaluated the clinicopathologic correlation and prognostic significance of MST1/2 and LATS1/2 immunohistochemical expressions in 327 colorectal cancer patients. Low MST1/2 expression, identified in 235 (71.9 %) cases, was significantly associated with poor differentiation (P = 0.018) and large size (P < 0.001) of the tumor. Negative LATS1/2 expression, identified in 226 (69.1 %) cases, was significantly correlated with low MST1/2 expression (P = 0.044). Low MST1/2 and negative LATS1/2 expressions were significantly associated with poor overall survivals (P = 0.015 and P = 0.038, respectively). Furthermore, the combined MST1/2lowLATS1/2negative expression group showed significantly worse overall survival than other groups (P = 0.003), and considered as an independent poor prognostic factor for colorectal cancer patients (hazard ratio = 1.720; 95 % confidence interval, 1.143-2.588; P = 0.009). Low MST1/2 and negative LATS1/2 expressions may serve as prognostic indicators in patients with colorectal cancer.

Improving the anti-tumor effect of EGCG in colorectal cancer cells by blocking EGCG-induced YAP activation.

(-)-Epigallocatechin-3-gallate (EGCG) is the primary active ingredient in green tea and has been used for cancer prevention in clinical trials. The anti-tumor effects of EGCG stem from its ability to inhibit the activities of many oncoproteins, such as AKT, VEGFR, STAT3, and mutant p53. However, the clinical efficacy of EGCG is unsatisfactory. How to improve the anti-tumor effects of EGCG is an open question. Here we report that EGCG inhibits the tumor suppressive Hippo signaling pathway and activates downstream YAP in colorectal cancer (CRC) cells. Activation of YAP impedes the anti-tumor effects of EGCG. YAP blockade increases the sensitivity of CRC cells to EGCG treatment.

Pharmacological Activation of YAP/TAZ by Targeting LATS1/2 Enhances Periodontal Tissue Regeneration in a Murine Model.

Due to their multi-differentiation potential, periodontal ligament fibroblasts (PDLF) play pivotal roles in periodontal tissue regeneration in vivo. Several in vitro studies have suggested that PDLFs can transmit mechanical stress into favorable basic cellular functions. However, the application of mechanical force for periodontal regeneration therapy is not expected to exhibit an effective prognosis since mechanical forces, such as traumatic occlusion, also exacerbate periodontal tissue degeneration and loss. Herein, we established a standardized murine periodontal regeneration model and evaluated the regeneration process associated with cementum remodeling. By administering a kinase inhibitor of YAP/TAZ suppressor molecules, such as large tumor suppressor homolog 1/2 (LATS1/2), we found that the activation of YAP/TAZ, a key downstream effector of mechanical signals, accelerated periodontal tissue regeneration due to the activation of PDLF cell proliferation. Mechanistically, among six kinds of MAP4Ks previously reported as upstream kinases that suppressed YAP/TAZ transcriptional activity through LATS1/2 in various types of cells, MAP4K4 was identified as the predominant MAP4K in PDLF and contributed to cell proliferation and differentiation depending on its kinase activity. Ultimately, pharmacological activation of YAP/TAZ by inhibiting upstream inhibitory kinase in PDLFs is a valuable strategy for improving the clinical outcomes of periodontal regeneration therapies.

Expression of the Hippo Pathway Core Components in Endometrial Cancer and Its Association with Clinicopathologic Features.

BACKGROUND: The Hippo signaling pathway has a key role in tumorigenesis. This study aimed to evaluate the relationship between the expression of core components of the Hippo signaling pathway and its association with clinicopathological features in endometrial cancer. MATERIALS AND METHODS: We retrospectively collected endometrioid endometrial cancer specimens from 60 patients between January 2002 and December 2009 at Gyeongsang National University Hospital. Relevant clinicopathological data were obtained through electronic medical records of patients. The expression patterns of six core components (YAP, p-YAP, LATS1/2, MST1/2, KIBRA, and Merlin) were identified by immunohistochemistry on tissue microarray sections. RESULTS: The positive expression ratio was 75.0% for YAP, 73.3% for p-YAP, 26.7% for MST1/2, 16.7% for KIBRA, 15.0% for Merlin, and 15.0% for LATS1/2. YAP expression was negatively correlated with MST 1/2 kinases (p = 0.045) and positively correlated with p-YAP (p = 0.012). Merlin, and MST 1/2 kinases (p = 0.043) showed a positive correlation. A subgroup of patients aged below 60 years (p = 0.004) and with myometrial invasion depth of less than 1/2 (p = 0.041) showed a positive association with YAP expression. p-YAP expression was negatively associated with a subset of patients with primary tumour size ≥4 cm (p = 0.03). Logistic regression analysis showed a significant association between age and YAP expression. The odds ratio of p-YAP expression was significantly lower in the group with tumour size ≥4 cm. CONCLUSION: Two prognostic factors, age and tumour size, were significantly associated with the expression of YAP and p-YAP in endometrial cancer. Further research should focus on their expression as a marker for prediction of clinicopathological implications in endometrial cancer.

Targeted Disruption of Lats1 and Lats2 in Mice Impairs Testis Development and Alters Somatic Cell Fate.

Hippo signaling plays an essential role in the development of numerous tissues. Although it was previously shown that the transcriptional effectors of Hippo signaling Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) can fine-tune the regulation of sex differentiation genes in the testes, the role of Hippo signaling in testis development remains largely unknown. To further explore the role of Hippo signaling in the testes, we conditionally deleted the key Hippo kinases large tumor suppressor homolog kinases 1 and -2 (Lats1 and Lats2, two kinases that antagonize YAP and TAZ transcriptional co-regulatory activity) in the somatic cells of the testes using an Nr5a1-cre strain (Lats1flox/flox;Lats2flox/flox;Nr5a1-cre). We report here that early stages of testis somatic cell differentiation were not affected in this model but progressive testis cord dysgenesis was observed starting at gestational day e14.5. Testis cord dysgenesis was further associated with the loss of polarity of the Sertoli cells and the loss of SOX9 expression but not WT1. In parallel with testis cord dysgenesis, a loss of steroidogenic gene expression associated with the appearance of myofibroblast-like cells in the interstitial space was also observed in mutant animals. Furthermore, the loss of YAP phosphorylation, the accumulation of nuclear TAZ (and YAP) in both the Sertoli and interstitial cell populations, and an increase in their transcriptional co-regulatory activity in the testes suggest that the observed phenotype could be attributed at least in part to YAP and TAZ. Taken together, our results suggest that Hippo signaling is required to maintain proper differentiation of testis somatic cells.

Hippo Signaling in the Ovary: Emerging Roles in Development, Fertility, and Disease.

Emerging studies indicate that the Hippo pathway, a highly conserved pathway that regulates organ size control, plays an important role in governing ovarian physiology, fertility, and pathology. Specific to the ovary, the spatiotemporal expression of the major components of the Hippo signaling cascade are observed throughout the reproductive lifespan. Observations from multiple species begin to elucidate the functional diversity and molecular mechanisms of Hippo signaling in the ovary in addition to the identification of interactions with other signaling pathways and responses to various external stimuli. Hippo pathway components play important roles in follicle growth and activation, as well as steroidogenesis, by regulating several key biological processes through mechanisms of cell proliferation, migration, differentiation, and cell fate determination. Given the importance of these processes, dysregulation of the Hippo pathway contributes to loss of follicular homeostasis and reproductive disorders such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency, and ovarian cancers. This review highlights what is currently known about the Hippo pathway core components in ovarian physiology, including ovarian development, follicle development, and oocyte maturation, while identifying areas for future research to better understand Hippo signaling as a multifunctional pathway in reproductive health and biology.

Fragment-based exploration of the 14-3-3/Amot-p130 interface.

The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as 'undruggable' targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the 'tractability' of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the 'ligandability' of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues.

Targeting the Hippo pathway in heart repair.

The Hippo pathway is an evolutionarily and functionally conserved signalling pathway that controls organ size by regulating cell proliferation, apoptosis, and differentiation. Emerging evidence has shown that the Hippo pathway plays critical roles in cardiac development, homeostasis, disease, and regeneration. Targeting the Hippo pathway has tremendous potential as a therapeutic strategy for treating intractable cardiovascular diseases, such as heart failure. In this review, we summarize the function of the Hippo pathway in the heart. Particularly, we highlight the post-translational modification of Hippo pathway components, including the core kinases LATS1/2 and their downstream effectors YAP/TAZ, in different contexts, which has provided new insights and avenues in cardiac research.

The two sides of Hippo pathway in cancer.

The Hippo signaling pathway was originally characterized by genetic studies in Drosophila to regulate tissue growth and organ size, and the core components of this pathway are highly conserved in mammals. Studies over the past two decades have revealed critical physiological and pathological functions of the Hippo tumor-suppressor pathway, which is tightly regulated by a broad range of intracellular and extracellular signals. These properties enable the Hippo pathway to serve as an important controller in organismal development and adult tissue homeostasis. Dysregulation of the Hippo signaling has been observed in many cancer types, suggesting the possibility of cancer treatment by targeting the Hippo pathway. The general consensus is that Hippo has tumor suppressor function. However, growing evidence also suggests that the function of the Hippo pathway in malignancy is cancer context dependent as recent studies indicating tumor promoting function of LATS. This article surveys the Hippo pathway signaling mechanisms and then reviews both the tumor suppressing and promoting function of this pathway. A comprehensive understanding of the dual roles of the Hippo pathway in cancer will benefit future therapeutic targeting of the Hippo pathway for cancer treatment.

Activation of the Hippo Pathway in Rana sylvatica: Yapping Stops in Response to Anoxia.

Wood frogs (Rana sylvatica) display well-developed anoxia tolerance as one component of their capacity to endure prolonged whole-body freezing during the winter months. Under anoxic conditions, multiple cellular responses are triggered to efficiently cope with stress by suppressing gene transcription and promoting activation of mechanisms that support cell survival. Activation of the Hippo signaling pathway initiates a cascade of protein kinase reactions that end with phosphorylation of YAP protein. Multiple pathway components of the Hippo pathway were analyzed via immunoblotting, qPCR or DNA-binding ELISAs to assess the effects of 24 h anoxia and 4 h aerobic recovery, compared with controls, on liver and heart metabolism of wood frogs. Immunoblot results showed significant increases in the relative levels of multiple proteins of the Hippo pathway representing an overall activation of the pathway in both organs under anoxia stress. Upregulation of transcript levels further confirmed this. A decrease in YAP and TEAD protein levels in the nuclear fraction also indicated reduced translocation of these proteins. Decreased DNA-binding activity of TEAD at the promoter region also suggested repression of gene transcription of its downstream targets such as SOX2 and OCT4. Furthermore, changes in the protein levels of two downstream targets of TEAD, OCT4 and SOX2, established regulated transcriptional activity and could possibly be associated with the activation of the Hippo pathway. Increased levels of TAZ in anoxic hearts also suggested its involvement in the repair mechanism for damage caused to cardiac muscles during anoxia. In summary, this study provides the first insights into the role of the Hippo pathway in maintaining cellular homeostasis in response to anoxia in amphibians.

YAP/Hippo Pathway and Cancer Immunity: It Takes Two to Tango.

Hippo pathway with its main molecule YAP is a crucial pathway for development, tissue homeostasis, wound healing, tissue regeneration, and cancer. In this review, we discuss the multiple effects of the YAP/Hippo pathway in the immune system and cancer. We analyzed a series of effects: extracellular vesicles enhanced immunity through inhibition of LATS1/2, ways of modulation of the tumor microenvironment, YAP- and TAZ-mediated upregulation of PDL1, high expression of YAP and PDL1 in EGFR-TKI-resistant cells, enhanced YAP activity in inflammation, and the effect of the Hippo pathway on T cells, B cells, Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs). These pleiotropic effects render the YAP and Hippo pathway a key pathway for exploitation in the future, in order to enhance our immunotherapy treatment strategies in oncology.

RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2.

Around 70% of breast cancers express the estrogen receptor alpha (ERα). This receptor is of central importance for breast cancer development and estrogen-dependent tumor growth. However, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast carcinogenesis are complex and not fully understood. In previous work, we have demonstrated that the tumor suppressor RASSF1A suppresses estrogen-dependent growth of breast cancer cells through a complex network that keeps ERα expression and function under control. We observed that RASSF1A mediates the suppression of ERα expression through modulation of the Hippo effector Yes-associated protein 1 (YAP1) activity. Here we report that RASSF1A-mediated alteration of YAP1 depends on the Hippo-kinases LATS1 and LATS2. Based on these results, we conclude that inactivation of RASSF1A causes changes in the function of the Hippo signaling pathway and altered activation of YAP1, and as a consequence, increased expression and function of ERα. Thus, the inactivation of RASSF1A might constitute a fundamental event that supports the initiation of ERα-dependent breast cancer. Furthermore, our results support the notion that the Hippo pathway is important for the suppression of luminal breast cancers, and that the tumor-suppressor function of RASSF1A depends on LATS1 and LATS2.

Hippo Signaling Pathway in Pancreas Development.

The Hippo signaling pathway is a vital regulator of pancreatic development and homeostasis, directing cell fate decisions, morphogenesis, and adult pancreatic cellular plasticity. Through loss-of-function research, Hippo signaling has been found to play key roles in maintaining the proper balance between progenitor cell renewal, proliferation, and differentiation in pancreatic organogenesis. Other studies suggest that overactivation of YAP, a downstream effector of the pathway, promotes ductal cell development and suppresses endocrine cell fate specification via repression of Ngn3. After birth, disruptions in Hippo signaling have been found to lead to de-differentiation of acinar cells and pancreatitis-like phenotype. Further, Hippo signaling directs pancreatic morphogenesis by ensuring proper cell polarization and branching. Despite these findings, the mechanisms through which Hippo governs cell differentiation and pancreatic architecture are yet to be fully understood. Here, we review recent studies of Hippo functions in pancreatic development, including its crosstalk with NOTCH, WNT/ß-catenin, and PI3K/Akt/mTOR signaling pathways.

The Chlamydia trachomatis Tarp effector targets the Hippo pathway.

Chlamydia trachomatis injects bacterial effector proteins into human epithelial cells to facilitate the establishment of new infections. The chlamydial type III secreted effector translocated actin recruiting phosphoprotein (Tarp) has been shown to nucleate and bundle actin filaments. It is also believed to initiate new signaling pathways via an N-terminal phosphorylation domain. A comprehensive understanding of the host pathways that are controlled by Tarp to aid in the establishment of a successful infection remains incomplete. To gain further insight into the cell signaling regulated by Tarp, we generated transgenic fruit flies engineered to express the N-terminal domain of Tarp. As many signaling pathways are conserved between flies and mammals, we hypothesized that expression of the Tarp N-domain in the fruit fly might disrupt key pathways, resulting in developmental defects. Tarp N-domain expression in the fruit fly resulted in a mechanosensory bristle duplication phenotype similar to a previously characterized fly phenotype found to be a consequence of defects in the Hippo pathway. Tarp-dependent disruption of the Hippo pathway was confirmed in a C. trachomatis tissue culture infection model. The capability of Tarp to alter Hippo pathway signaling in infected epithelial cells is a previously unrecognized pathway commandeered by chlamydia and likely contributes to the establishment of chlamydia's intracellular niche.

A Comparative Analysis of Hippo Signaling Pathway Components during Murine and Bovine Early Mammalian Embryogenesis.

The time required for successful blastocyst formation varies among multiple species. The formation of a blastocyst is governed by numerous molecular cell signaling pathways, such as the Hippo signaling pathway. The Hippo signaling pathway is initiated by increased cell-cell contact and via apical polarity proteins (AMOT, PARD6, and NF2) during the period of preimplantation embryogenesis. Cell-cell contact and cell polarity activate (phosphorylates) the core cascade components of the pathway (mammalian sterile twenty like 1 and 2 (MST1/2) and large tumor suppressor 1 and 2 (LATS1/2)), which in turn phosphorylate the downstream effectors of the pathway (YAP1/TAZ). The Hippo pathway remains inactive with YAP1 (Yes Associated protein 1) present inside the nucleus in the trophectoderm (TE) cells (polar blastomeres) of the mouse blastocyst. In the inner cell mass (ICM) cells (apolar blastomeres), the pathway is activated with p-YAP1 present in the cytoplasm. On the contrary, during bovine embryogenesis, p-YAP1 is exclusively present in the nucleus in both TE and ICM cells. Contrary to mouse embryos, transcription co activator with PDZ-binding motif (TAZ) (also known as WWTR1) is also predominantly present in the cytoplasm in all the blastomeres during bovine embryogenesis. This review outlines the major differences in the localization and function of Hippo signaling pathway components of murine and bovine preimplantation embryos, suggesting significant differences in the regulation of this pathway in between the two species. The variance observed in the Hippo signaling pathway between murine and bovine embryos confirms that both of these early embryonic models are quite distinct. Moreover, based on the similarity of the Hippo signaling pathway between bovine and human early embryo development, bovine embryos could be an alternate model for understanding the regulation of the Hippo signaling pathway in human embryos.

Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors.

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.

Hippo Signaling Pathway in Gliomas.

The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.