TAZ is indispensable for c-MYC-induced hepatocarcinogenesis

Wang, Haichuan; Zhang, Shanshan; Zhang, Yi; Jia, Jiaoyuan; Wang, Jingxiao; Liu, Xianqiong; Zhang, Jie; Song, Xinhua; Ribback, Silvia; Cigliano, Antonio; Evert, Matthias; Liang, Binyong; Wu, Hong; Calvisi, Diego F.; Zeng, Yong

doi:10.1016/j.jhep.2021.08.021

Cited by 30 publications

(19 citation statements)

References 27 publications

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“…In addition, similar to YAP, simultaneous upregulation of AKT in TAZ-overexpressing mouse livers induced rapid cholangiocarcinogenesis, suggesting the requirement of AKT for TAZ and YAP full oncogenic potential. According to this hypothesis, previous evidence from our laboratory indicates that TAZ can induce hepatocellular carcinoma and hepatoblastoma development in the mouse via hydrodynamic transfection only in association with other molecular events, such as overexpression of c-Myc, c-Met, and mutant β-catenin, or loss of APC [ 33 , 46 , 47 ]. The cellular and molecular mechanisms induced by collaborating oncogenes allowing TAZ to express its malignant properties remain unaddressed.…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

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Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined. Methods We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP. Results Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis. Conclusions Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis

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Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

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“…Unlike the recognition mechanism, cell shape change and cytoskeleton proteins involved in the extrusion seem to be a consensus. Prior to the extrusion, calcium wave arises from the transformed cell and propagates across the surrounding cells (Takeuchi et al 2020 ), consistent with the critical role of calcium signaling in controlling cytoskeleton protein (Wales et al 2016 ). Upregulation of calcium levels induces the F-actin accumulation in the cytosol and perinuclear region in the surrounding normal cells.…”

Section: Different Modes Of Cell Competition Between Cancer Cells And...mentioning

confidence: 80%

Pleiotropic effects of cell competition between normal and transformed cells in mammalian cancers

Zhang

Zhu

2022

J Cancer Res Clin Oncol

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“…The Hippo signaling pathway is thought to function as a major tumor suppressor pathway by inhibiting hepatocyte proliferation, survival, and invasion and hepatocellular carcinogenesis. HCC samples showed increased expression of the Hippo pathway effectors YAP and TAZ [ 7 ], which is associated with poor overall survival; for example, TAZ plays an essential role in c-MYC-induced hepatocarcinogenesis [ 28 ]. Furthermore, hepatocyte plasticity and differentiation-specific hepatocarcinogenesis are determined by Yap-Sox9 signaling [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis

Liu

Zang

et al. 2023

Cell Death Dis

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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. The Hippo signaling pathway has emerged as a significant suppressive pathway for hepatocellular carcinogenesis. The core components of the Hippo pathway constitute a kinase cascade, which inhibits the functional activation of YAP/TAZ. Interestingly, the overactivation of YAP/TAZ is commonly observed in hepatocellular carcinoma, although the inhibitory kinase cascade of the Hippo pathway is still functional. Recent studies have indicated that the ubiquitin‒proteasome system also plays important roles in modulating Hippo signaling activity. Our DUB (deubiquitinase) siRNA screen showed that USP1 is a critical regulator of Hippo signaling activity. Analysis of TCGA data demonstrated that USP1 expression is elevated in HCC and associated with poor survival in HCC patients. RNA sequencing analysis revealed that USP1 depletion affects Hippo signaling activity in HCC cell lines. Mechanistic assays revealed that USP1 is required for Hippo/TAZ axis activity and HCC progression. USP1 interacted with the WW domain of TAZ, which subsequently enhanced TAZ stability by suppressing K11-linked polyubiquitination of TAZ. Our study identifies a novel mechanism linking USP1 and TAZ in regulating the Hippo pathway and one possible therapeutic target for HCC.

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TAZ is indispensable for c-MYC-induced hepatocarcinogenesis

Cited by 30 publications

References 27 publications

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Pleiotropic effects of cell competition between normal and transformed cells in mammalian cancers

USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis

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