Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

Ehmer, Ursula; Sage, Julien

doi:10.1158/1541-7786.mcr-15-0305

Cited by 127 publications

(110 citation statements)

References 163 publications

(246 reference statements)

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“…Our results support a link between YAP1 overexpression and acquisition of a stem cell trait by HCC and the hypothesis [58] that YAP1 upregulation in HCC exhibits a critical oncogenic role in a complex signaling network triggering fast growth and invasiveness.…”

Section: Discussionsupporting

confidence: 89%

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

et al. 2016

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Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.

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Section: Discussionsupporting

confidence: 89%

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

et al. 2016

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“…CD31) (14,15) is a possible mechanism underlying the inactivation of the Hippo pathway in human angiosarcoma. YAP is one of the core components of the Hippo pathway (28,29,37) and nuclear YAP localization indicates Hippo pathway inactivation. (14,15,18,21) As a possible mechanism for survivin expression in angiosarcoma, we assumed YAP nuclear translocation, namely, Hippo pathway inactivation, because survivin is one of the YAP target genes.…”

Section: Discussionmentioning

confidence: 99%

Survivin: A novel marker and potential therapeutic target for human angiosarcoma

et al. 2017

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Human angiosarcoma is a rare malignant vascular tumor associated with extremely poor clinical outcome and generally arising in skin of the head and neck region. However, little is known about the molecular pathogeneses and useful immunohistochemical markers of angiosarcoma. To investigate the mechanisms of angiosarcoma progression, we collected 85 cases of human angiosarcoma specimens with clinical records and analyzed ISO‐HAS‐B patient‐derived angiosarcoma cells. As control subjects, 54 cases of hemangioma and 34 of pyogenic granuloma were collected. Remarkably, consistent with our recent observations regarding the involvement of survivin expression following Hippo pathway inactivation in the neoplastic proliferation of murine hemangioendothelioma cells and human infantile hemangioma, nuclear survivin expression was observed in all cases of angiosarcoma but not in hemangiomas and pyogenic granulomas, and the Hippo pathway was inactivated in 90.3% of yes‐associated protein (YAP) ‐positive angiosarcoma cases. However, survivin expression modes and YAP localization (Hippo pathway activation modes) were not correlated with survival. In addition, we confirmed that survivin small interference RNA (siRNA) transfection and YM155, an anti‐survivin drug, elicited decreased nuclear survivin expression and cell proliferation in ISO‐HAS‐B cells which expressed survivin consistently. Conclusively, these findings support the importance of survivin as a good marker and critical regulator of cellular proliferation for human angiosarcoma and YM155 as a potential therapeutic agent.

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“…NF2 regulates multiple signaling pathways, including the Hippo pathway ( Fig. 7A) (19,20). YAP is a potent transcription coactivator and the main downstream target of the Hippo pathway, acting via binding to the transcriptional enhancer associated domain (TEAD) transcription factor.…”

Section: Nf2 and Yap Regulate The Levels Of Arih1 And Eif4e2mentioning

confidence: 99%

Genome‐wide screening identifies novel genes and biological processes implicated in cisplatin resistance

Ko¹,

Li²

2019

FASEB j.

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Cisplatin‐based chemotherapeutic regimens are frequently used for treatments of solid tumors. However, tumor cells may have inherent or acquired cisplatin resistance, and the underlying mechanisms are largely unknown. We performed genome‐wide screening of genes implicated in cisplatin resistance in A375 human melanoma cells. A substantial fraction of genes whose disruptions cause cisplatin sensitivity or resistance overlap with those whose disruptions lead to increased or decreased cell growth, respectively. Protein translation, mitochondrial respiratory chain complex assembly, signal recognition particle‐dependent cotranslational protein targeting to membrane, and mRNA catabolic processes are the top biologic processes responsible for cisplatin sensitivity. In contrast, proteasome‐mediated ubiquitin‐dependent protein catabolic process, negative regulations of cellular catabolic process, and regulation of cellular protein localization are the top biologic processes responsible for cisplatin resistance. ZNRF3, a ubiquitin ligase known to be a target and negative feedback regulator of Wnt–β‐catenin signaling, enhances cisplatin resistance in normal and melanoma cells independently of β‐catenin. Ariadne‐1 homolog (ARIH1), another ubiquitin ligase, also enhances cisplatin resistance in normal and melanoma cells. By regulating ARIH1, neurofibromin 2, a tumor suppressor, enhances cisplatin resistance in melanoma but not normal cells. Our results shed new lights on cisplatin resistance mechanisms and may be useful for development of cisplatin‐related treatment strategies.—Ko, T., Li, S. Genome‐wide screening identifies novel genes and biological processes implicated in cisplatin resistance. FASEB J. 33, 7143–7154 (2019). http://www.fasebj.org

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Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

Cited by 127 publications

References 163 publications

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Survivin: A novel marker and potential therapeutic target for human angiosarcoma

Genome‐wide screening identifies novel genes and biological processes implicated in cisplatin resistance

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