Multiple roles and context-specific mechanisms underlying YAP and TAZ-mediated resistance to anti-cancer therapy

Reggiani, Francesca; Gobbi, Giulia; Ciarrocchi, Alessia; Ambrosetti, Davide Carlo; Sancisi, Valentina

doi:10.1016/j.bbcan.2020.188341

Cited by 21 publications

(16 citation statements)

References 131 publications

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“…Therefore, eliminating senescent cells in a precise way enables the maximization of therapeutic efficacy. On the other hand, targeting the YAP1/TEAD expression and their transcriptional activity by BET inhibitors are proposed as promising strategies to overcome chemo-resistance 53,54 .…”

Section: Discussionmentioning

confidence: 99%

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

et al. 2021

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Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-XL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.

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Section: Discussionmentioning

confidence: 99%

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

et al. 2021

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“…YAP is a transcription coregulator downstream of the Hippo pathway and plays a critical role in cancer ( 34 ). Additionally, TAZ is involved in mediating resistance to several anticancer drugs ( 35 ). Previous studies have indicated that the YAP/TAZ axis may serve a key role in cancer, via modulating the cell proliferation, cell survival and cancer cell stemness ( 30 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have indicated that the YAP/TAZ axis may serve a key role in cancer, via modulating the cell proliferation, cell survival and cancer cell stemness (30,36). YAP/TAZ signaling participates in metabolic pathways, mechanical stimulation, tumorigenesis, drug resistance and immune escape (35). In particular, YAP and TAZ have been associated with several cellular processes involved in promoting cancer development and aggressiveness/metastasis, including cancer stemness and EMT (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

lncRNA KCNQ1OT1 promotes proliferation and invasion of glioma cells by targeting the miR‑375/YAP pathway

et al. 2020

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The long non-coding RNA KCNQ1OT1 is generally recognized as an oncogenic molecule in several human malignant tumors. However, to the best of our knowledge, the role of KCNQ1OT1 in glioma has not been fully investigated. The current study aimed to probe the biological function of KCNQ1OT1 in human glioma cell lines and its mechanisms. The glioma cell lines U251 and U87-MG were used as cell models. Cell proliferation and apoptosis assays were used to measure the effects of different treatments on survival, and reverse transcription-quantitative PCR and western blot-ting were used to investigate the expression profiles of key molecules. Migration and invasion assays were conducted to reveal the biological features of glioma cells. The results indicated that KCNQ1OT1 was upregulated in glioma tissues compared with adjacent tissues, which was associated with poor prognosis. Additionally, knockdown of KCNQ1OT1 in U251 and U87-MG cells inhibited cell proliferation, migration and invasion, but had no effect on apoptosis. The effects of KCNQ1OT1 on migration and invasion were partially attributed to enhanced Yes-associated protein (YAP) expression levels and epithelial-mesenchymal transition (EMT) signaling. Furthermore, microRNA (miR)-375 functioned as a link between KCNQ1OT1 and YAP in regulating cell proliferation. Finally, the KCNQ1OT1/miR-375/YAP axis modulated cell proliferation and cell fate by affecting the modulated YAP-mediated EMT signaling. In conclusion, the KCNQ1OT1/miR-375/YAP axis modulated migration and invasion of glioma cells by affecting EMT signaling; thus, targeting KCNQ1OT1 may represent a promising strategy in glioma therapeutics.

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“…The description of the detailed mechanisms underlying YAP-induced therapy resistance vary but they converge on one common theme: YAP/TAZ-mediated transcription is upregulated and responsible—either by the inactivation of upstream Hippo proteins or other negative YAP regulators or by direct YAP/TAZ activation [ 71 , 72 , 73 , 74 ]. While mutations in negative YAP regulators such as PTPN14 in relapsed neuroblastomas can lead to upregulated YAP transcriptional activity at relapse [ 9 ], not all YAP-expressing neuroblastomas harbor PTPN14 mutations and the exact mechanism as to how YAP induces therapy resistance in neuroblastoma may be context-dependent based on the type of chemotherapy or targeted therapy used [ 71 , 72 ].…”

Section: Yap and Its Role In High-risk Neuroblastomamentioning

confidence: 99%

“…The dysregulation of Hippo signaling and subsequent activation of YAP/TAZ is a major resistance mechanism identified in response to multiple targeted therapies [ 71 , 72 , 73 , 74 ]. Two of the most studied targeted therapies in the context of YAP deregulation in cancers is EGFR and MAPK pathway inhibitors.…”

Section: Yap and Its Role In High-risk Neuroblastomamentioning

confidence: 99%

A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment

Shim

Goldsmith

2021

Cancers

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Neuroblastoma is the most common extra-cranial pediatric solid tumor that accounts for more than 15% of childhood cancer-related deaths. High risk neuroblastomas that recur during or after intense multimodal therapy have a <5% chance at a second sustained remission or cure. The solid tumor microenvironment (TME) has been increasingly recognized to play a critical role in cancer progression and resistance to therapy, including in neuroblastoma. The Yes-Associated Protein (YAP) in the Hippo pathway can regulate cancer proliferation, tumor initiation, and therapy response in many cancer types and as such, its role in the TME has gained interest. In this review, we focus on YAP and its role in neuroblastoma and further describe its demonstrated and potential effects on the neuroblastoma TME. We also discuss the therapeutic strategies for inhibiting YAP in neuroblastoma.

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Multiple roles and context-specific mechanisms underlying YAP and TAZ-mediated resistance to anti-cancer therapy

Cited by 21 publications

References 131 publications

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

lncRNA KCNQ1OT1 promotes proliferation and invasion of glioma cells by targeting the miR‑375/YAP pathway

A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment

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