Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Holden, Jeffrey K.; Cunningham, Christian N.

doi:10.3390/cancers10030081

Cited by 140 publications

(106 citation statements)

References 72 publications

(127 reference statements)

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“…The TEAD protein family consists of four paralogous factors that function as nuclear DNA-binding proteins to modulate transcriptional activity of downstream genes in response to Hippo signaling pathway. Of note, the modulated role of TEAD depends on binding with TAZ or YAP in nucleus whose nuclear importation is mediated by LATS1/2 16,17,44 . MiRNAs participate in numerous biological processes, including tumor initiation, progression and metastasis 24,[32][33][34]59 .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, GAS1 and LATS2 were veri ed as downstream targets of miR-942-3p directly. LATS2 could suppress the transcriptional activation of Hippo pathway-related gene by phosphorylating TAZ 9,14,44 . Interestingly, GAS1 acted as a key regulator in cell migration, EMT and glycometabolism in colorectal cancer cells 41 .…”

Section: Discussionmentioning

confidence: 99%

“…3f and 3g). TAZ interacts with the TEAD to recruit to their target promoters and regulate gene expression 16,17,44 . Therefore, we predicted the binding site of TEADs in the promoter region of miR-942 in JASPAR (Fig.…”

Section: Mir-942-3p Is Regulated By Taz-teadmentioning

confidence: 99%

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A positive feedback loop between TAZ and miR-942-3p modulates proliferation, migration, epithelial-mesenchymal transition process and glycometabolism in human bladder cancer

Wang

Fan

Zhou

et al. 2020

Preprint

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Background: Transcriptional co-activator with PDZ-binding motif (TAZ) has been reported to involve in tumor progression, epithelial-mesenchymal transition (EMT) process and glycometabolism modulation. Herein, the underlying molecular mechanisms of TAZ-induced biological effects in bladder cancer were discovered; Methods: qRT-PCR, western blot and immunohistochemistry were performed to determine the level of TAZ in bladder cancer cells and tissues; CCK-8 assay, Colony formation assay, wound healing assay and Transwell assay were performed to evaluate the functions of TAZ, miR-942-3p and GAS1. qRT-PCR and western blot were used to determine the expression levels of related genes. Chromatin immunoprecipitation and dual-luciferase reporter assay confirmed the interaction between TAZ and miR-942. In vivo tumorigenesis assay and colorimetric assay of glycolysis were also conducted; Results: We determined the upregulation and vital roles of TAZ in bladder cancer. TAZ-induced upregulation of miR-942-3p amplified upstream signaling by inhibiting the expression of large tumor suppressor 2 (LATS2, a TAZ inhibitor). MiR-942-3p attenuated the suppression of cell proliferation, EMT process and glycolysis induced by TAZ knockdown. Further, miR-942-3p resulted in restrained expression of growth arrest-specific 1 (GAS1) to modulate biological functions; Conclusion: Our study identified a novel positive feedback loop between TAZ and miR-942-3p that regulates biological functions in bladder cancer cells via GAS1 expression, and illustrated that TAZ and miR-942-3p might be potential therapeutic targets for bladder cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A positive feedback loop between TAZ and miR-942-3p modulates proliferation, migration, epithelial-mesenchymal transition process and glycometabolism in human bladder cancer

Wang

Fan

Zhou

et al. 2020

Preprint

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“…Dysregulation of the Hippo pathway is implicated in a wide range of human cancers [ 1–4 ]. Targetting this pathway with small molecules may lead to novel therapeutic interventions for the treatment of human diseases [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Activation mechanisms of the Hippo kinase signaling cascade

Bae

Luo

2018

Bioscience Reports

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First discovered two decades ago through genetic screens in Drosophila, the Hippo pathway has been shown to be conserved in metazoans and controls organ size and tissue homeostasis through regulating the balance between cell proliferation and apoptosis. Dysregulation of the Hippo pathway leads to aberrant tissue growth and tumorigenesis. Extensive studies in Drosophila and mammals have identified the core components of Hippo signaling, which form a central kinase cascade to ultimately control gene expression. Here, we review recent structural, biochemical, and cellular studies that have revealed intricate phosphorylation-dependent mechanisms in regulating the formation and activation of the core kinase complex in the Hippo pathway. These studies have established the dimerization-mediated activation of the Hippo kinase (mammalian Ste20-like 1 and 2 (MST1/2) in mammals), the dynamic scaffolding and allosteric roles of adaptor proteins in downstream kinase activation, and the importance of multisite linker autophosphorylation by Hippo and MST1/2 in fine-tuning the signaling strength and robustness of the Hippo pathway. We highlight the gaps in our knowledge in this field that will require further mechanistic studies.

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“…YAP, TAZ, and TEAD represent the most relevant functional proteins in the signaling system and their role as drug targets have been validated [ 6 ]. Owing to its relevance, several drug discovery programs aimed to identify new small molecules that can target the YAP/TAZ/TEAD network, effectively impairing the TEAD function [ 7 , 8 ]. However, only recently, some systematic approaches of drug discovery have led to a few leads that will be further developed.…”

Section: Introductionmentioning

confidence: 99%

Repurposing of Drugs Targeting YAP-TEAD Functions

Elisi

Santucci

D’Arca

et al. 2018

Cancers

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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.

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Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Cited by 140 publications

References 72 publications

A positive feedback loop between TAZ and miR-942-3p modulates proliferation, migration, epithelial-mesenchymal transition process and glycometabolism in human bladder cancer

A positive feedback loop between TAZ and miR-942-3p modulates proliferation, migration, epithelial-mesenchymal transition process and glycometabolism in human bladder cancer

Activation mechanisms of the Hippo kinase signaling cascade

Repurposing of Drugs Targeting YAP-TEAD Functions

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