Abstract
YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including 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 involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Ewing sarcoma (EwS) represents the second most common primary malignant bone tumor in children and young adults [1]
Basal and luminal breast cancer (MDA-MB-231, MCF-7), prostate cancer (PC3), osteosarcoma (SA-OS-2), rhabdomyosarcoma (RH30), and human mesenchymal stem cells were included in the assay. (B) Nucleus and cytoplasm subcellular lysates were assessed by western blotting (WB) (T, total extract; N, nucleus; C, cytoplasm). (C) Immunofluorescence images using the indicated antibodies (60× original objective magnification). (D) YAP1/TAZ-TEAD-dependent transcriptional activity in EwS cell lines was evaluated with luciferase reporter constructs containing sequences with or without TEAD elements (8×TEAD and TnT-minP constructs, respectively)
We have shown that YAP1/TAZ nuclear expression is associated with disease progression and poor prognosis in a large retrospective series of EwS patients
Summary
Ewing sarcoma (EwS) represents the second most common primary malignant bone tumor in children and young adults [1]. The most common somatic mutations have been detected in STAG2, CDKN2A, and TP53, associated with poor prognosis [6,7]. 99 (EE99) and EWING 2008 trials showed that chromosome 1q gain and possibly chromosome 16q loss define patients with a poor clinical outcome (Díaz-Martín et al, unpublished data), supporting previous retrospective studies [7,8]. G. 99 (EE99) and EWING 2008 trials showed that chromosome 1q gain and possibly chromosome 16q loss define patients with a poor clinical outcome (Díaz-Martín et al, unpublished data), supporting previous retrospective studies [7,8] These secondary alterations occur with a frequency that does not account for the large proportion of patients who relapse
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
