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Cancers
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Hippo Signaling Pathway in Cancers
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Hippo Signaling Pathway in Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 41081

Special Issue Editor

Dr. Joachim Kremerskothen

E-Mail Website
Guest Editor
Universitätsklinikum Münster, Munster, Germany
Interests: Inter- and intracellular control of YAP/TAZ transcriptional activity; WWC proteins as regulators of Hippo signaling; Regulated degradation of Hippo pathway components; Hippo signaling in postmitotic cells; Mechanical cues and Hippo signaling

Special Issue Information

Dear Colleagues,

The Hippo signaling pathway is known to regulate cell differentiation, cell proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to cytoplasmic retention of the transcriptional coactivators YAP and TAZ, decreased Hippo signaling results in nuclear import of YAP/TAZ and the subsequent transcription of pro-proliferative genes. Hence, a dynamic and precise regulation of the Hippo signaling pathway is not only crucial for proper organ size control but prevents uncontrolled cell proliferation and tumor formation.

The first components and regulatory mechanisms of the Hippo signaling pathway were described in Drosophila melanogaster more than two decades ago. Genomic screening identified the serine/threonine kinases Warts (Wts; Lats1/2 in mammals) and Hippo (Hpo; Mst1/2 in mammals) as components of a kinase cascade the negatively controls cell proliferation and enhances apoptosis due to reduced transcription of pro-proliferative genes. The transcriptional coactivator Yorkie (Yki; YAP/TAZ in mammalian cells) was identified later as the missing link between the kinase cascade activity and transcriptional regulation.

A disturbed Hippo pathway contributes to a variety of human diseases including cancer. Key components of the Hippo pathway including Lats1/2 and Mst1/2 act as tumor suppressors and their impaired expression or enhanced protein degradation are involved in elevated nuclear YAP/TAZ activity and subsequent tumor formation. Therefore, pharmaceutical approaches to treat Hippo-dependent tumor formation target the stabilization and activation of crucial components and/or the inhibition of nuclear YAP/TAZ activity.

This Special Issue will summarize the current knowledge on Hippo signaling in de-regulated cell proliferation and tumor formation.  It will elucidate the complexity of Hippo signaling with a focus on the interplay of different signaling systems and cellular processes. Furthermore, the reader will get an update on the approaches to identify therapeutic targets within the Hippo pathway for intervention in human cancer.

Dr. Joachim Kremerskothen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • The Hippo pathway and cell fate determination
  • Hippo signaling and cell cycle control
  • YAP/TAZ target genes with an impact on tumor formation
  • Crosstalk between Hippo, Notch and Wnt signaling in cancer
  • Hippo signaling, inflammation and cancer
  • Hippo signaling in solid and soft tissue tumors
  • Hippo signaling and leukemia
  • Targeting Hippo signaling for pharmaceutical intervention in cancer

Published Papers (10 papers)

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Research

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22 pages, 15220 KiB  
Article
Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery
by Jongwan Kim, Hocheol Lim, Sungho Moon, Seon Yeon Cho, Minhye Kim, Jae Hyung Park, Hyun Woo Park and Kyoung Tai No
Cancers 2021, 13(16), 4246; https://doi.org/10.3390/cancers13164246 - 23 Aug 2021
Cited by 20 | Viewed by 4228
Abstract
The Hippo pathway is an important signaling pathway modulating growth control and cancer cell proliferation. Dysregulation of the Hippo pathway is a common feature of several types of cancer cells. The modulation of the interaction between yes-associated protein (YAP) and transcriptional enhancer associated [...] Read more.
The Hippo pathway is an important signaling pathway modulating growth control and cancer cell proliferation. Dysregulation of the Hippo pathway is a common feature of several types of cancer cells. The modulation of the interaction between yes-associated protein (YAP) and transcriptional enhancer associated domain (TEAD) in the Hippo pathway is considered an attractive target for cancer therapeutic development, although the inhibition of PPI is a challenging task. In order to investigate the hot spots of the YAP and TEAD1 interacting complex, an ab initio Fragment Molecular Orbital (FMO) method was introduced. With the hot spots, pharmacophores for the inhibitor design were constructed, then virtual screening was performed to an in-house library. Next, we performed molecular docking simulations and FMO calculations for screening results to study the binding modes and affinities between PPI inhibitors and TEAD1. As a result of the virtual screening, three compounds were selected as virtual hit compounds. In order to confirm their biological activities, cellular (luciferase activity, proximity ligation assay and wound healing assay in A375 cells, qRT-PCR in HEK 293T cells) and biophysical assays (surface plasmon resonance assays) were performed. Based on the findings of the study, we propose a novel PPI inhibitor BY03 and demonstrate a profitable strategy to analyze YAP–TEAD PPI and discover novel PPI inhibitors. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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21 pages, 20959 KiB  
Article
miR-582-5p Is a Tumor Suppressor microRNA Targeting the Hippo-YAP/TAZ Signaling Pathway in Non-Small Cell Lung Cancer
by Bowen Zhu, Mitheera V, Megan Finch-Edmondson, Yaelim Lee, Yue Wan, Marius Sudol and Ramanuj DasGupta
Cancers 2021, 13(4), 756; https://doi.org/10.3390/cancers13040756 - 11 Feb 2021
Cited by 20 | Viewed by 3818
Abstract
The Hippo-YAP/TAZ signaling pathway is an evolutionarily conserved signaling pathway involved in a broad spectrum of biological processes, including tumorigenesis. Whilst aberrant Hippo-YAP/TAZ signaling is frequently reported in various cancers, the genetic alterations of this pathway are relatively rare, suggesting regulation at the [...] Read more.
The Hippo-YAP/TAZ signaling pathway is an evolutionarily conserved signaling pathway involved in a broad spectrum of biological processes, including tumorigenesis. Whilst aberrant Hippo-YAP/TAZ signaling is frequently reported in various cancers, the genetic alterations of this pathway are relatively rare, suggesting regulation at the post-transcriptional level. MicroRNAs play key role in tumorigenesis by regulating gene expression post-transcriptionally. Amongst the cancer-relevant microRNAs, miR-582-5p suppresses cell growth and tumorigenesis by inhibiting the expression of oncogenes, including AKT3, MAP3K2 and NOTCH1. Given the oncogenic role of YAP/TAZ in solid tumors, we scrutinized the possible interplay between miR-582-5p and Hippo-YAP/TAZ signaling. Correlation analysis in NSCLC cells revealed a positive relationship between the expression of mature miR-582-5p and the proportion of phosphorylated YAP/TAZ. Intriguingly, YAP/TAZ knockdown reduced the expression of mature miR-582-5p but increased that of primary miR-582. Overexpression of miR-582-5p resulted in increased phosphorylation of YAP/TAZ with a concomitant reduction in cell proliferation and enhanced apoptosis. Mechanistically, we find that miR-582-5p targets actin regulators NCKAP1 and PIP5K1C, which may be responsible for the observed alteration in F-actin, known to modulate YAP/TAZ. We postulate that regulation of the actin cytoskeleton by miR-582-5p may attenuate YAP/TAZ activity. Altogether, this study reveals a novel mechanism of YAP/TAZ regulation by miR-582-5p in a cytoskeleton-dependent manner and suggests a negative feedback loop, highlighting the therapeutic potential of restoring miR-582-5p expression in treating NSCLC. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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15 pages, 2352 KiB  
Article
Common and Unique Transcription Signatures of YAP and TAZ in Gastric Cancer Cells
by Yaelim Lee, Megan Finch-Edmondson, Hamizah Cognart, Bowen Zhu, Haiwei Song, Boon Chuan Low and Marius Sudol
Cancers 2020, 12(12), 3667; https://doi.org/10.3390/cancers12123667 - 7 Dec 2020
Cited by 10 | Viewed by 3128
Abstract
YAP and its paralog TAZ are the nuclear effectors of the Hippo tumour-suppressor pathway, and function as transcriptional co-activators to control gene expression in response to mechanical cues. To identify both common and unique transcriptional targets of YAP and TAZ in gastric cancer [...] Read more.
YAP and its paralog TAZ are the nuclear effectors of the Hippo tumour-suppressor pathway, and function as transcriptional co-activators to control gene expression in response to mechanical cues. To identify both common and unique transcriptional targets of YAP and TAZ in gastric cancer cells, we carried out RNA-sequencing analysis of overexpressed YAP or TAZ in the corresponding paralogous gene-knockouts (KOs), TAZ KO or YAP KO, respectively. Gene Ontology (GO) analysis of the YAP/TAZ-transcriptional targets revealed activation of genes involved in platelet biology and lipoprotein particle formation as targets that are common for both YAP and TAZ. However, the GO terms for cell-substrate junction were a unique function of YAP. Further, we found that YAP was indispensable for the gastric cancer cells to re-establish cell-substrate junctions on a rigid surface following prolonged culture on a soft substrate. Collectively, our study not only identifies common and unique transcriptional signatures of YAP and TAZ in gastric cancer cells but also reveals a dominant role for YAP over TAZ in the control of cell-substrate adhesion. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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18 pages, 3089 KiB  
Article
USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer
by Ashley Mussell, He Shen, Yanmin Chen, Michalis Mastri, Kevin H. Eng, Wiam Bshara, Costa Frangou and Jianmin Zhang
Cancers 2020, 12(11), 3090; https://doi.org/10.3390/cancers12113090 - 23 Oct 2020
Cited by 34 | Viewed by 3630
Abstract
The Hippo signaling pathway is an evolutionarily conserved pathway that was initially discovered in Drosophila melanogaster and was later found to have mammalian orthologues. The key effector proteins in this pathway, YAP/TAZ, are often dysregulated in cancer, leading to a high degree of [...] Read more.
The Hippo signaling pathway is an evolutionarily conserved pathway that was initially discovered in Drosophila melanogaster and was later found to have mammalian orthologues. The key effector proteins in this pathway, YAP/TAZ, are often dysregulated in cancer, leading to a high degree of cell proliferation, migration, metastasis and cancer stem cell populations. Due to these malignant phenotypes it is important to understand the regulation of YAP/TAZ at the protein level. Using an siRNA library screen of deubiquitinating enzymes (DUBs), we identified ubiquitin specific peptidase 1 (USP1) as a novel TAZ (WWTR1) regulator. We demonstrated that USP1 interacts with TAZ and increases TAZ protein stability. Conversely, loss of function of USP1 reduces TAZ protein levels through increased poly-ubiquitination, causing a decrease in cell proliferation and migration of breast cancer cells. Moreover, we showed a strong positive correlation between USP1 and TAZ in breast cancer patients. Our findings facilitate the attainment of better understanding of the crosstalk between these pathways and may lead to potential therapeutic interventions for breast cancer patients. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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Review

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30 pages, 1051 KiB  
Review
Genetic Alterations and Deregulation of Hippo Pathway as a Pathogenetic Mechanism in Bone and Soft Tissue Sarcoma
by Carmen Salguero-Aranda, Joaquín Olmedo-Pelayo, Enrique de Álava, Ana Teresa Amaral and Juan Díaz-Martín
Cancers 2022, 14(24), 6211; https://doi.org/10.3390/cancers14246211 - 15 Dec 2022
Cited by 2 | Viewed by 1997
Abstract
The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. [...] Read more.
The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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16 pages, 840 KiB  
Review
Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ–CAMTA1 Fusion Driven Sarcoma
by Caleb N. Seavey, Ajaybabu V. Pobbati and Brian P. Rubin
Cancers 2022, 14(12), 2980; https://doi.org/10.3390/cancers14122980 - 16 Jun 2022
Cited by 7 | Viewed by 3096
Abstract
The activities of YAP and TAZ, the end effectors of the Hippo pathway, are consistently altered in cancer, and this dysregulation drives aggressive tumor phenotypes. While the actions of these two proteins aid in tumorigenesis in the majority of cancers, the dysregulation of [...] Read more.
The activities of YAP and TAZ, the end effectors of the Hippo pathway, are consistently altered in cancer, and this dysregulation drives aggressive tumor phenotypes. While the actions of these two proteins aid in tumorigenesis in the majority of cancers, the dysregulation of these proteins is rarely sufficient for initial tumor development. Herein, we present a unique TAZ-driven cancer, epithelioid hemangioendothelioma (EHE), which harbors a WWTR1(TAZ)–CAMTA1 gene fusion in at least 90% of cases. Recent investigations have elucidated the mechanisms by which YAP/TAP-fusion oncoproteins function and drive tumorigenesis. This review presents a critical evaluation of this recent work, with a particular focus on how the oncoproteins alter the normal activity of TAZ and YAP, and, concurrently, we generate a framework for how we can target the gene fusions in patients. Since EHE represents a paradigm of YAP/TAZ dysregulation in cancer, targeted therapies for EHE may also be effective against other YAP/TAZ-dependent cancers. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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27 pages, 1191 KiB  
Review
The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective
by Yi Xiao and Jixin Dong
Cancers 2021, 13(24), 6214; https://doi.org/10.3390/cancers13246214 - 10 Dec 2021
Cited by 24 | Viewed by 6229
Abstract
Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell [...] Read more.
Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell cycle regulation in tumors has led to the development of powerful anti-cancer drugs. Therefore, an in-depth exploration of cell cycle dysregulation in cancers could provide therapeutic avenues for cancer treatment. The Hippo pathway is an evolutionarily conserved regulator network that controls organ size, and its dysregulation is implicated in various types of cancers. Although the role of the Hippo pathway in oncogenesis has been widely investigated, its role in cell cycle regulation has not been comprehensively scrutinized. Here, we specifically focus on delineating the involvement of the Hippo pathway in cell cycle regulation. To that end, we first compare the structural as well as functional conservation of the core Hippo pathway in yeasts, flies, and mammals. Then, we detail the multi-faceted aspects in which the core components of the mammalian Hippo pathway and their regulators affect the cell cycle, particularly with regard to the regulation of E2F activity, the G1 tetraploidy checkpoint, DNA synthesis, DNA damage checkpoint, centrosome dynamics, and mitosis. Finally, we briefly discuss how a collective understanding of cell cycle regulation and the Hippo pathway could be weaponized in combating cancer. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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23 pages, 777 KiB  
Review
The Hippo Signaling Pathway in Drug Resistance in Cancer
by Renya Zeng and Jixin Dong
Cancers 2021, 13(2), 318; https://doi.org/10.3390/cancers13020318 - 16 Jan 2021
Cited by 41 | Viewed by 5487
Abstract
Chemotherapy represents one of the most efficacious strategies to treat cancer patients, bringing advantageous changes at least temporarily even to those patients with incurable malignancies. However, most patients respond poorly after a certain number of cycles of treatment due to the development of [...] Read more.
Chemotherapy represents one of the most efficacious strategies to treat cancer patients, bringing advantageous changes at least temporarily even to those patients with incurable malignancies. However, most patients respond poorly after a certain number of cycles of treatment due to the development of drug resistance. Resistance to drugs administrated to cancer patients greatly limits the benefits that patients can achieve and continues to be a severe clinical difficulty. Among the mechanisms which have been uncovered to mediate anti-cancer drug resistance, the Hippo signaling pathway is gaining increasing attention due to the remarkable oncogenic activities of its components (for example, YAP and TAZ) and their druggable properties. This review will highlight current understanding of how the Hippo signaling pathway regulates anti-cancer drug resistance in tumor cells, and currently available pharmacological interventions targeting the Hippo pathway to eradicate malignant cells and potentially treat cancer patients. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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16 pages, 987 KiB  
Review
WWC Proteins: Important Regulators of Hippo Signaling in Cancer
by Verena Höffken, Anke Hermann, Hermann Pavenstädt and Joachim Kremerskothen
Cancers 2021, 13(2), 306; https://doi.org/10.3390/cancers13020306 - 15 Jan 2021
Cited by 28 | Viewed by 3973
Abstract
The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to phosphorylation and cytoplasmic retention of the transcriptional coactivator YAP, decreased Hippo signaling results in nuclear import of YAP and subsequent transcription [...] Read more.
The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to phosphorylation and cytoplasmic retention of the transcriptional coactivator YAP, decreased Hippo signaling results in nuclear import of YAP and subsequent transcription of pro-proliferative genes. Hence, a dynamic and precise regulation of the Hippo signaling pathway is crucial for organ size control and the prevention of tumor formation. The transcriptional activity of YAP is controlled by a growing number of upstream regulators including the family of WWC proteins. WWC1, WWC2 and WWC3 represent cytosolic scaffolding proteins involved in intracellular transport processes and different signal transduction pathways. Earlier in vitro experiments demonstrated that WWC proteins positively regulate the Hippo pathway via the activation of large tumor suppressor kinases 1/2 (LATS1/2) kinases and the subsequent cytoplasmic accumulation of phosphorylated YAP. Later, reduced WWC expression and subsequent high YAP activity were shown to correlate with the progression of human cancer in different organs. Although the function of WWC proteins as upstream regulators of Hippo signaling was confirmed in various studies, their important role as tumor modulators is often overlooked. This review has been designed to provide an update on the published data linking WWC1, WWC2 and WWC3 to cancer, with a focus on Hippo pathway-dependent mechanisms. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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18 pages, 2925 KiB  
Review
YAP/TAZ Signalling in Colorectal Cancer: Lessons from Consensus Molecular Subtypes
by Sophie Mouillet-Richard and Pierre Laurent-Puig
Cancers 2020, 12(11), 3160; https://doi.org/10.3390/cancers12113160 - 28 Oct 2020
Cited by 14 | Viewed by 4054
Abstract
Recent advance in the characterization of the heterogeneity of colorectal cancer has led to the definition of a consensus molecular classification within four CMS subgroups, each associated with specific molecular and clinical features. Investigating the signalling pathways that drive colorectal cancer progression in [...] Read more.
Recent advance in the characterization of the heterogeneity of colorectal cancer has led to the definition of a consensus molecular classification within four CMS subgroups, each associated with specific molecular and clinical features. Investigating the signalling pathways that drive colorectal cancer progression in relation to the CMS classification may help design therapeutic strategies tailored for each CMS subtype. The two main effectors of the Hippo pathway YAP and its paralogue TAZ have been intensively scrutinized for their contribution to colon carcinogenesis. Here, we review the knowledge of YAP/TAZ implication in colorectal cancer from the perspective of the CMS framework. We identify gaps in our current understanding and delineate research avenues for future work. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)
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