The sweet side of YAP/TAZ

Santinon, Giulia; Enzo, Elena; Dupont, Sirio

doi:10.1080/15384101.2015.1062328

Cited by 8 publications

(6 citation statements)

References 6 publications

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“…4D ). However, the depletion of TAZ, a another cofactor that binds to TEADs 24 25 , failed to abrogate the hypoxic resistance towards sorafenib, with similar inhibition rates of sorafenib in NC siRNA and TAZ siRNA cells under hypoxia ( Figure S1 ).To further validate the involvement of the YAP target genes in the apoptosis caused by the combination treatment, the target genes with anti-apoptotic functions- Bcl-xl, CTGF, and Cyr61 26 27 28 29 -were investigated. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells

Zhou

Zhuang

et al. 2016

Sci Rep

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Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients.

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Section: Resultsmentioning

confidence: 99%

Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells

Zhou

Zhuang

et al. 2016

Sci Rep

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“…The goal is to promote tumor invasion, progression, and metastasis [ 116 ]. This process is influenced and regulated by YAP/TAZ since these work as nuclear and transcriptional mediators in different metabolic routes, promoting thesupress transcription of target genes that allow cells to adapt to the changing conditions of the tissue [ 117 , 118 ]. The role of these transcription cofactors in glycolysis, which is the main pathway used by tumor cells for sustained proliferation, stands out [ 119 ].…”

Section: Remodelling Of the Tumor Microenvironmentmentioning

confidence: 99%

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

Ortega

Vera

Díaz

et al. 2021

IJMS

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The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways’ role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.

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“…Metabolic reprogramming is crucial for maintaining the stemness of CSC (Folmes et al, 2012;Wu et al, 2015;Sancho et al, 2016). Recently, Hippo pathway transcription factors YAP and TAZ emerged as crucial mediator of the metabolic control of CSC selfrenewal (Sorrentino et al, 2014;Enzo et al, 2015;Mo et al, 2015;Santinon et al, 2015Santinon et al, , 2016. Interestingly, DGUOK depletion significantly reduced the protein levels of YAP1 (but not that of TAZ) ( Fig 4A), inhibited the nuclear translocation of YAP1 (Figs 4B and EV4A) and reduced the mRNA transcript levels of YAP/TAZ target genes CTGF and CYR61 ( Fig 4C), indicating inhibition of YAP1 signaling in DGUOK KO cells.…”

Section: Dguok Depletion Inhibits Yap1 Signaling Through Activation Omentioning

confidence: 99%

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

et al. 2019

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The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate‐limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self‐renewal of lung cancer stem‐like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self‐renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self‐renewal through AMPK‐YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK‐mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline‐inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC‐mediated therapy resistance and metastatic recurrence.

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The sweet side of YAP/TAZ

Abstract: Editorially invited Comment on\ud Aerobic glycolysis tunes YAP/TAZ transcriptional activity. [EMBO J. 2015

Cited by 8 publications

References 6 publications

Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells

Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

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