WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma

Driskill, Jordan H.; Zheng, Yonggang; Wu, Baichang; Wang, Li; Cai, Jing; Rakheja, Dinesh; Dellinger, Michael T.; Pan, Duojia

doi:10.1101/gad.348221.120

Cited by 41 publications

(42 citation statements)

References 57 publications

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“…Findings from our study are consistent with recent reports that demonstrate a crucial role for TAZ in cancers. For example, the fusion of the TAZ gene with the gene that encodes CAMTA1 transcription factor is responsible for the majority of cases documenting a rare tumor known as Epithelioid Hemangio-Endothelioma (EHE) that primarily affects soft tissues, including lung [ 57 , 58 ]. Altogether, our findings highlight the important function of SFTA1P in a TAZ-dependent regulation of Hippo-YAP/TAZ signaling and NSCLC tumorigenesis, which warrants further study.…”

Section: Discussionmentioning

confidence: 99%

LncRNA SFTA1P mediates positive feedback regulation of the Hippo-YAP/TAZ signaling pathway in non-small cell lung cancer

et al. 2021

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Long non-coding RNAs (lncRNAs) regulate numerous biological processes involved in both development and carcinogenesis. Hippo-YAP/TAZ signaling, a critical pathway responsible for organ size control, is often dysregulated in a variety of cancers. However, the nature and function of YAP/TAZ-regulated lncRNAs during tumorigenesis remain largely unexplored. By profiling YAP/TAZ-regulated lncRNAs, we identified SFTA1P as a novel transcriptional target and a positive feedback regulator of YAP/TAZ signaling. Using non-small cell lung cancer (NSCLC) cell lines, we show that SFTA1P is transcriptionally activated by YAP/TAZ in a TEAD-dependent manner. Functionally, knockdown of SFTA1P in NSCLC cell lines inhibited proliferation, induced programmed cell death, and compromised their tumorigenic potential. Mechanistically, SFTA1P knockdown decreased TAZ protein abundance and consequently, the expression of YAP/TAZ transcriptional targets. We provide evidence that this phenomenon could potentially be mediated via its interaction with TAZ mRNA to regulate TAZ translation. Our results reveal SFTA1P as a positive feedback regulator of Hippo-YAP/TAZ signaling, which may serve as the molecular basis for lncRNA-based therapies against YAP/TAZ-driven cancers.

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Section: Discussionmentioning

confidence: 99%

LncRNA SFTA1P mediates positive feedback regulation of the Hippo-YAP/TAZ signaling pathway in non-small cell lung cancer

et al. 2021

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“…In a different study, Driskill et al generated an overexpression system for TC expression based on a Tet-Off approach [ 92 ]. Concordant with the findings of Seavey et al, this study demonstrated that TC expression is lethal during embryogenesis.…”

Section: Novel Model Systems For Studying Ehe Biologymentioning

confidence: 99%

“…If the TC fusion protein is controlled by these regulators, the action of TC could be diminished, either by the inhibition of the negative regulators of the Hippo pathway, or by positive regulators of TC. Despite the initial suggestion that TC is unregulated by the Hippo pathway, recent evidence suggests that Hippo alters the action of TC [ 92 ]. In unpublished work, via co-immunoprecipitation followed by mass spectrometry, we have seen that the TC protein is phosphorylated at the regulatory S89 residue and that it associates with the 14-3-3 protein [ 97 ].…”

Section: Development Of Targeted Therapiesmentioning

confidence: 99%

“…This work was further corroborated by Driskill et al, who showed that TC associates with subunits of the 14-3-3 complex. They also showed both the enhanced nuclear localization of TC in LATS knockout cells compared with that in LATS wild-type cells, and the enhanced nuclear localization and transcriptional activity of the fusion protein upon the mutation of the serine residues within TC, which are phosphorylated by LATS [ 92 ]. Therefore, it is becoming more evident that, even though TC is localized predominantly to the nucleus, it is not completely dissociated from the regulation of the Hippo pathway.…”

Section: Development Of Targeted Therapiesmentioning

confidence: 99%

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Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ–CAMTA1 Fusion Driven Sarcoma

Seavey

Pobbati

Rubin

2022

Cancers

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The activities of YAP and TAZ, the end effectors of the Hippo pathway, are consistently altered in cancer, and this dysregulation drives aggressive tumor phenotypes. While the actions of these two proteins aid in tumorigenesis in the majority of cancers, the dysregulation of these proteins is rarely sufficient for initial tumor development. Herein, we present a unique TAZ-driven cancer, epithelioid hemangioendothelioma (EHE), which harbors a WWTR1(TAZ)–CAMTA1 gene fusion in at least 90% of cases. Recent investigations have elucidated the mechanisms by which YAP/TAP-fusion oncoproteins function and drive tumorigenesis. This review presents a critical evaluation of this recent work, with a particular focus on how the oncoproteins alter the normal activity of TAZ and YAP, and, concurrently, we generate a framework for how we can target the gene fusions in patients. Since EHE represents a paradigm of YAP/TAZ dysregulation in cancer, targeted therapies for EHE may also be effective against other YAP/TAZ-dependent cancers.

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“…Moreover, several previous reports have demonstrated the roles of YAP [ 10 , 11 , 12 , 13 , 14 , 15 ] and TAZ [ 16 , 17 , 18 ] in mature endothelial cells and the angiogenic process. Even though YAP and TAZ possess less than 60% amino acid sequence similarity, they are often considered to control the same group of target genes and have similar functions [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Distinctive Roles of YAP and TAZ in Human Endothelial Progenitor Cells Growth and Functions

et al. 2022

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The hippo signaling pathway plays an essential role in controlling organ size and balancing tissue homeostasis. Its two main effectors, yes-associated protein (YAP) and WW domain-containing transcription regulator 1, WWTR1 or TAZ, have also been shown to regulate endothelial cell functions and angiogenesis. In this study, the functions of YAP and TAZ in human endothelial progenitor cells (EPCs) were investigated by a loss-of-function study using CRISPR/Cas9-mediated gene knockdown (KD). Depletion of either YAP or TAZ reduced EPC survival and impaired many of their critical functions, including migration, invasion, vessel-formation, and expression of pro-angiogenic genes. Notably, TAZ-KD EPCs exhibited more severe phenotypes in comparison to YAP-KD EPCs. Moreover, the conditioned medium derived from TAZ-KD EPCs reduced the survivability of human lung cancer cells and increased their sensitivity to chemotherapeutic agents. The overexpression of either wild-type or constitutively active TAZ rescued the impaired phenotypes of TAZ-KD EPCs and restored the expression of pro-angiogenic genes in those EPCs. In summary, we demonstrate the crucial role of Hippo signaling components, YAP and TAZ, in controlling several aspects of EPC functions that can potentially be used as a drug target to enhance EPC functions in patients.

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WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma

Cited by 41 publications

References 57 publications

LncRNA SFTA1P mediates positive feedback regulation of the Hippo-YAP/TAZ signaling pathway in non-small cell lung cancer

LncRNA SFTA1P mediates positive feedback regulation of the Hippo-YAP/TAZ signaling pathway in non-small cell lung cancer

Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ–CAMTA1 Fusion Driven Sarcoma

Distinctive Roles of YAP and TAZ in Human Endothelial Progenitor Cells Growth and Functions

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