Special Issue "Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (28 February 2018)

Special Issue Editor

Guest Editor
Prof. Yutaka Hata

Department of Medical Biochemistry, Graduate School of Medicine Tokyo Medical and Dental University, Tokyo, Japan
Website | E-Mail
Interests: signal transduction; tumor suppressor; cell junction

Special Issue Information

Dear Colleagues,

The Hippo pathway is the newest and possibly be the last addition to signalling pathways, which have ever been growing. We know now that the fundamental role of the pathway is the negative regulation of two transcription regulators, YAP1 and TAZ. YAP1/TAZ co-operate with TEAD and other transcription factors to regulate cell proliferation and differentiation.

Human cancers are frequently associated with deregulation of the Hippo pathway. The consequent hyperactivation of YAP1/TAZ and TEAD induces epithelial-mesenchymal transition and enhances drug resistance. Accordingly, the incidence of metastasis and recurrence is increased. It is reasonable to assume that inhibition of YAP1/TAZ and TEAD improves prognosis in cancer patients.

Hence, the development of drugs that target YAP1/TAZ and TEAD is one of the current topics in cancer therapy. Such reagents are indeed reported but are presumably the tip of the iceberg. We can imagine that the more promising candidates would be the more strictly kept in secrecy at this stage. Certain promising drugs may be developing, though we have yet to see the results.

If we wait, such new drugs may join to our arsenal in the fight against cancer.  However, we cannot be too optimistic; to realize the Hippo-targeted therapy, there are several barriers to clear. We need to identify good druggable targets. To obtain approval for drugs, we are required to clearly demonstrate their superiority over conventional drugs. It is also a good strategy to repurpose the already approved drugs as the Hippo-targeted drugs. To avoid severe side effects, we must understand precisely how the activation of the Hippo pathway affects cancer pathophysiology.

This Special Issue will highlight a part of the efforts of researchers towards the realization of Hippo-targeted therapy and provide a forum for brainstorming.

Prof. Yutaka Hata
Guest Editor

Manuscript Submission Information

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Published Papers (13 papers)

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Editorial

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Open AccessEditorial Hippo Pathway in Cancer, towards the Realization of Hippo-Targeted Therapy
Cancers 2018, 10(10), 383; https://doi.org/10.3390/cancers10100383
Received: 8 October 2018 / Accepted: 10 October 2018 / Published: 12 October 2018
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Research

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Open AccessArticle Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface
Cancers 2018, 10(5), 140; https://doi.org/10.3390/cancers10050140
Received: 24 April 2018 / Revised: 3 May 2018 / Accepted: 4 May 2018 / Published: 8 May 2018
Cited by 3 | PDF Full-text (3257 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. [...] Read more.
Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP50–71-hTEAD1209–426 complex (PDB 3KYS) published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds) was screened against this hydrophobic pocket of TEAD. Four different chemical families have been identified and evaluated using biophysical techniques (thermal shift assay, microscale thermophoresis) and in cellulo assays (luciferase activity in transfected HEK293 cells, RTqPCR in MDA-MB231 cells). A first promising hit with micromolar inhibition in the luciferase gene reporter assay was discovered. This hit also decreased mRNA levels of TEAD target genes. Full article
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Review

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Open AccessReview Repurposing of Drugs Targeting YAP-TEAD Functions
Cancers 2018, 10(9), 329; https://doi.org/10.3390/cancers10090329
Received: 4 August 2018 / Revised: 7 September 2018 / Accepted: 7 September 2018 / Published: 14 September 2018
Cited by 1 | PDF Full-text (5029 KB) | HTML Full-text | XML Full-text
Abstract
Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway’s terminal effectors, namely YAP (Yes1-associated [...] Read more.
Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway’s terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology. Moreover, this could be relevant to obtain new molecular tools and potential therapeutic assets. In this review, we discuss the main mechanisms of action of the best-known compounds, clinically approved or investigational drugs, able to cross-talk and modulate the Hippo pathway, as an attractive strategy for the discovery of new potential lead compounds. Full article
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Open AccessFeature PaperReview Epithelioid Hemangioendothelioma as a Model of YAP/TAZ-Driven Cancer: Insights from a Rare Fusion Sarcoma
Cancers 2018, 10(7), 229; https://doi.org/10.3390/cancers10070229
Received: 1 June 2018 / Revised: 8 July 2018 / Accepted: 9 July 2018 / Published: 10 July 2018
Cited by 2 | PDF Full-text (1306 KB) | HTML Full-text | XML Full-text
Abstract
Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central [...] Read more.
Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central nervous system-specific transcription activator. The 10% of EHEs that lack the TAZ–CAMTA1 fusion instead have a fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3). YAP and TAZ are well-defined downstream effectors in the Hippo pathway that promote cell growth when translocated to the nucleus. The TAZ–CAMTA1 fusion transcript is insensitive to the Hippo inhibitory signals that normally prevent this process and thus constitutively activates the TAZ transcriptome. In EHE, this causes tumors to form in a variety of organs and tissue types, most commonly the liver, lung, and bone. Its clinical course is unpredictable and highly variable. TAZ activation is known to contribute to key aspects of the cancer phenotype, including metastasis and fibrosis, and increased expression of TAZ is thought to be causally related to the progression of many cancers, including breast, lung, and liver. Therefore, understanding TAZ biology and the molecular mechanisms by which it promotes unregulated cell proliferation will yield insights and possibly improved treatments for both EHE as well as much more common cancers. Full article
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Open AccessReview YAP and TAZ in Lung Cancer: Oncogenic Role and Clinical Targeting
Cancers 2018, 10(5), 137; https://doi.org/10.3390/cancers10050137
Received: 30 March 2018 / Revised: 1 May 2018 / Accepted: 2 May 2018 / Published: 6 May 2018
Cited by 4 | PDF Full-text (2367 KB) | HTML Full-text | XML Full-text
Abstract
Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance [...] Read more.
Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance to the treatment. Further knowledge of the mechanisms driving lung tumorigenesis, aggressiveness, metastasization, and resistance to treatments could provide new tools for detecting the disease at an earlier stage and for a better response to therapy. In this scenario, Yes Associated Protein (YAP) and Trascriptional Coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as promising therapeutic targets. Here, we will discuss the most recent advances made in YAP and TAZ biology in lung cancer and, more importantly, on the newly discovered mechanisms of YAP and TAZ inhibition in lung cancer as well as their clinical implications. Full article
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Open AccessReview Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer
Cancers 2018, 10(4), 121; https://doi.org/10.3390/cancers10040121
Received: 28 February 2018 / Revised: 8 April 2018 / Accepted: 13 April 2018 / Published: 17 April 2018
Cited by 2 | PDF Full-text (5735 KB) | HTML Full-text | XML Full-text
Abstract
The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the [...] Read more.
The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system. Full article
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Open AccessFeature PaperReview YAP/TAZ Activation as a Target for Treating Metastatic Cancer
Cancers 2018, 10(4), 115; https://doi.org/10.3390/cancers10040115
Received: 19 March 2018 / Revised: 1 April 2018 / Accepted: 3 April 2018 / Published: 10 April 2018
Cited by 8 | PDF Full-text (28465 KB) | HTML Full-text | XML Full-text
Abstract
Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or [...] Read more.
Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses. Full article
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Open AccessReview The Hippo Pathway: Immunity and Cancer
Received: 9 March 2018 / Revised: 23 March 2018 / Accepted: 26 March 2018 / Published: 28 March 2018
Cited by 6 | PDF Full-text (13761 KB) | HTML Full-text | XML Full-text
Abstract
Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway [...] Read more.
Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work. Full article
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Open AccessFeature PaperReview Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma
Received: 28 February 2018 / Revised: 20 March 2018 / Accepted: 21 March 2018 / Published: 22 March 2018
Cited by 4 | PDF Full-text (12104 KB) | HTML Full-text | XML Full-text
Abstract
Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities and is highly refractory to conventional therapies. Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF, NF2 [...] Read more.
Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities and is highly refractory to conventional therapies. Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM. The NF2 gene encodes merlin, a protein that regulates multiple cell-signaling cascades including the Hippo pathway. MMs also exhibit inactivation of Hippo pathway components including LATS1/2, strongly suggesting that merlin-Hippo pathway dysregulation plays a key role in the development and progression of MM. Furthermore, Hippo pathway inactivation has been shown to result in constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells. Critical YAP1/TAZ target genes, including prooncogenic CCDN1 and CTGF, have also been shown to enhance the malignant phenotypes of MM cells. Together, these data indicate the Hippo pathway as a therapeutic target for the treatment of MM, and support the development of new strategies to effectively target the activation status of YAP1/TAZ as a promising therapeutic modality for this formidable disease. Full article
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Open AccessReview Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors
Received: 23 February 2018 / Revised: 15 March 2018 / Accepted: 16 March 2018 / Published: 20 March 2018
Cited by 9 | PDF Full-text (2589 KB) | HTML Full-text | XML Full-text
Abstract
The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling [...] Read more.
The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo. Full article
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Open AccessReview Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond
Received: 4 January 2018 / Revised: 5 February 2018 / Accepted: 5 February 2018 / Published: 6 February 2018
Cited by 6 | PDF Full-text (4161 KB) | HTML Full-text | XML Full-text
Abstract
In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing [...] Read more.
In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing towards tissue fibrosis and cancer. The transcriptional co-activators YAP/TAZ, better known as the converging effectors of the Hippo pathway, are widely recognized for their new role as nuclear mechanosensors during organ homeostasis and cancer. Still, how YAP/TAZ senses these “stiffness cues” from the ECM remains enigmatic. Here, we highlight the recent perspectives on the role of agrin in mechanosignaling from the ECM via antagonizing the Hippo pathway to activate YAP/TAZ in the contexts of cancer, neuromuscular junctions, and cardiac regeneration. Full article
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Other

Open AccessCommentary WIP-YAP/TAZ as A New Pro-Oncogenic Pathway in Glioma
Cancers 2018, 10(6), 191; https://doi.org/10.3390/cancers10060191
Received: 24 April 2018 / Revised: 6 June 2018 / Accepted: 7 June 2018 / Published: 9 June 2018
Cited by 1 | PDF Full-text (664 KB) | HTML Full-text | XML Full-text
Abstract
Wild-type p53 (wtp53) is described as a tumour suppressor gene, and mutations in p53 occur in many human cancers. Indeed, in high-grade malignant glioma, numerous molecular genetics studies have established central roles of RTK-PI3K-PTEN and ARF-MDM2-p53 INK4a-RB pathways in promoting oncogenic capacity. Deregulation [...] Read more.
Wild-type p53 (wtp53) is described as a tumour suppressor gene, and mutations in p53 occur in many human cancers. Indeed, in high-grade malignant glioma, numerous molecular genetics studies have established central roles of RTK-PI3K-PTEN and ARF-MDM2-p53 INK4a-RB pathways in promoting oncogenic capacity. Deregulation of these signalling pathways, among others, drives changes in the glial/stem cell state and environment that permit autonomous growth. The initially transformed cell may undergo subsequent modifications, acquiring a more complete tumour-initiating phenotype responsible for disease advancement to stages that are more aggressive. We recently established that the oncogenic activity of mutant p53 (mtp53) is driven by the actin cytoskeleton-associated protein WIP (WASP-interacting protein), correlated with tumour growth, and more importantly that both proteins are responsible for the tumour-initiating cell phenotype. We reported that WIP knockdown in mtp53-expressing glioblastoma greatly reduced proliferation and growth capacity of cancer stem cell (CSC)-like cells and decreased CSC-like markers, such as hyaluronic acid receptor (CD44), prominin-1 (CD133), yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). We thus propose a new CSC signalling pathway downstream of mtp53 in which Akt regulates WIP and controls YAP/TAZ stability. WIP drives a mechanism that stimulates growth signals, promoting YAP/TAZ and β-catenin stability in a Hippo-independent fashion, which allows cells to coordinate processes such as proliferation, stemness and invasiveness, which are key factors in cancer progression. Based on this multistep tumourigenic model, it is tantalizing to propose that WIP inhibitors may be applied as an effective anti-cancer therapy. Full article
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Open AccessFeature PaperCommentary The Hippo-YAP Pathway Regulates 3D Organ Formation and Homeostasis
Cancers 2018, 10(4), 122; https://doi.org/10.3390/cancers10040122
Received: 6 March 2018 / Revised: 4 April 2018 / Accepted: 16 April 2018 / Published: 17 April 2018
Cited by 2 | PDF Full-text (1465 KB) | HTML Full-text | XML Full-text
Abstract
The vertebrate body shape is formed by the specific sizes and shapes of its resident tissues and organs, whose alignments are essential for proper functioning. To maintain tissue and organ shape, and thereby function, it is necessary to remove senescent, transformed, and/or damaged [...] Read more.
The vertebrate body shape is formed by the specific sizes and shapes of its resident tissues and organs, whose alignments are essential for proper functioning. To maintain tissue and organ shape, and thereby function, it is necessary to remove senescent, transformed, and/or damaged cells, which impair function and can lead to tumorigenesis. However, the molecular mechanisms underlying three-dimensional (3D) organ formation and homeostasis are not fully clear. Yes-associated protein (YAP) is a transcriptional co-activator that is involved in organ size control and tumorigenesis. Recently, we reported that YAP is essential for proper 3D body shape through regulation of cell tension by using a unique medaka fish mutant, hirame (hir). In Madin–Darby canine kidney (MDCK) epithelial cells, active YAP-transformed cells are eliminated apically when surrounded by normal cells. Furthermore, in a mosaic mouse model, active YAP-expressing damaged hepatocytes undergo apoptosis and are eliminated from the liver. Thus, YAP functions in quantitative and quality control in organogenesis. In this review, we describe the various roles of YAP in vertebrates, including in the initiation of liver cancer. Full article
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