Artículo
Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma
Autor/es | Rodríguez-Núñez, Pablo
Romero Pérez, Laura Amaral, Ana T. Puerto-Camacho, Pilar Jordán, Carmen Marcilla, David Álava Casado, Enrique de Díaz-Martín, Juan |
Departamento | Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica |
Fecha de publicación | 2020 |
Fecha de depósito | 2023-06-14 |
Publicado en |
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Resumen | YAP1 and TAZ (WWTR1) oncoproteins are thefinal transducers of the Hippo tumor suppressor pathway. Deregula-tion of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, includ-ing ... YAP1 and TAZ (WWTR1) oncoproteins are thefinal transducers of the Hippo tumor suppressor pathway. Deregula-tion of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, includ-ing sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon.Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involvingthe geneEWSR1andFLI1as the most common partner. The fusion protein is a potent driver of oncogenesis, but sec-ondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse orprogression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 pri-mary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the diseaseand predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of theRASSF1locus (a regulator of the Hippo pathway) wasobserved in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethyla-tion ofRASSF1correlated with the transcriptional silencing of the tumor suppressor isoformRASFF1A, and tran-scriptional activation of the pro-tumorigenic isoformRASSF1C, which promotes YAP1/TAZ activation. Knockdownof YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcriptionactivity is inversely correlated with the EWS–FLI1 transcriptional signature. This transcriptional antagonism couldbe explained partly by EWS–FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the tran-scriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamicfluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS |
Agencias financiadoras | Asociacion Española Contra el Cancer (AECC) Asociacion Pablo Ugarte AECC project CIBERONC Fundacion Publica Andaluza Progreso y Salud (Junta de Andalucia) German Cancer Aid Hospital Universitario Virgen del Rocio-Instituto de Biomedicina de Sevilla Biobank (ISCIII-Red de Biobancos) Instituto de Salud Carlos III ISCIII-FEDER |
Identificador del proyecto | GCB13-1578
TPY-M 1149/13; TRPV 205/18 GCB13-1578 CB16/12/00361 DKH-70112257 PT17/0015/0041 PI16CIII/00026; DTS18CIII/00005 PI14/01466; PI17/00464 |
Cita | Rodríguez-Núñez, P., Romero Pérez, L., Amaral, A.T., Puerto-Camacho, P., Jordán, C., Marcilla, D.,...,Díaz-Martín, J. (2020). Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma. The Journal of Pathology, 250 (4), 374-386. https://doi.org/10.1002/path.5379. |
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