A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy

Pobbati, Ajaybabu V.; Hong, Wanjin

doi:10.7150/thno.40889

Cited by 164 publications

(141 citation statements)

References 157 publications

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“…Hereto, researches on Hippo signalling cascade may improve our understanding with regard to a variety of tumour properties including, but not limited to, metastasis, chemo‐resistance and EMT. Therefore, targeting Hippo may be an attractive option for cancer therapy 30 …”

Section: The Therapeutic Potential Of Lncrnas Involved In Hippo Pathwaymentioning

confidence: 99%

The crosstalk between lncRNAs and the Hippo signalling pathway in cancer progression

Yang

Lü

et al. 2020

Cell Proliferation

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LncRNAs play a pivotal role in the regulation of epigenetic modification, cell cycle, differentiation, proliferation, migration and other physiological activities. In particular, considerable studies have shown that the aberrant expression and dysregulation of lncRNAs are widely implicated in cancer initiation and progression by acting as tumour promoters or suppressors. Hippo signalling pathway has attracted researchers’ attention as one of the critical cancer‐related pathways in recent years. Increasing evidences have demonstrated that lncRNAs could interact with Hippo cascade and thereby contribute to acquisition of multiple malignant hallmarks, including proliferation, metastasis, relapse and resistance to anti‐cancer treatment. Specifically, Hippo signalling pathway is reported to modulate or be regulated by widespread lncRNAs. Intriguingly, certain lncRNAs could form a reciprocal feedback loop with Hippo signalling. More speculatively, lncRNAs related to Hippo pathway have been poised to become important putative biomarkers and therapeutic targets in human cancers. Herein, this review focuses on the crosstalk between lncRNAs and Hippo pathway in carcinogenesis, summarizes the comprehensive role of Hippo‐related lncRNAs in tumour progression and depicts their clinical diagnostic, prognostic or therapeutic potentials in tumours.

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Section: The Therapeutic Potential Of Lncrnas Involved In Hippo Pathwaymentioning

confidence: 99%

The crosstalk between lncRNAs and the Hippo signalling pathway in cancer progression

Yang

Lü

et al. 2020

Cell Proliferation

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“…The core of Hippo signaling is composed of a kinase cascade: the upstream phosphorylation kinase MST1/2 promotes LATS1/2 phosphorylation and activation, which subsequently phosphorylates the pathway effector YAP/TAZ and promotes YAP/TAZ retention in the cytosol and degradation 7 . But, If YAP/TAZ are not phosphorylated, they will trans-locate into the nuclear, interact with transcriptional factors, such as TEAD and RUNX to regulate genes involved in cell growth, migration, survival and metabolism 8 - 10 . Not surprisingly, dys-regulation of Hippo signaling has been implicated in many human cancers, including esophageal cancer 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2

Zhou¹,

Li²,

Wang³

et al. 2020

Theranostics

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Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. Methods: To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth in vivo . Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 in vivo . Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Results: Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P < 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Conclusion: Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox propo...

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“…Given the dual role of YAP – tumor suppression versus tumor promotion – in a cell type-specific manner, TONDU peptide-mediated therapeutic strategy may hold promise only in intestinal cancers that are mediated by the pro-tumorigenic YAP-TEAD complex. Indeed, a number of inhibitors targeting YAP/TAZ-TEAD complexes have now shown therapeutic promises in arresting growth of cancers, particularly those that display TEAD dependencies (for review, see Pobbati and Hong, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors

Bajpai

Ahmad

Tang

et al. 2020

Disease Models &Amp; Mechanisms

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Peptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven intestinal stem cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.This article has an associated First Person interview with the first author of the paper.

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A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy

Cited by 164 publications

References 157 publications

The crosstalk between lncRNAs and the Hippo signalling pathway in cancer progression

The crosstalk between lncRNAs and the Hippo signalling pathway in cancer progression

Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2

A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors

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