TY - JOUR
T1 - YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis
AU - Pajtler, Kristian W.
AU - Wei, Yiju
AU - Okonechnikov, Konstantin
AU - Silva, Patricia B.G.
AU - Vouri, Mikaella
AU - Zhang, Lei
AU - Brabetz, Sebastian
AU - Sieber, Laura
AU - Gulley, Melissa
AU - Mauermann, Monika
AU - Wedig, Tatjana
AU - Mack, Norman
AU - Imamura Kawasawa, Yuka
AU - Sharma, Tanvi
AU - Zuckermann, Marc
AU - Andreiuolo, Felipe
AU - Holland, Eric
AU - Maass, Kendra
AU - Körkel-Qu, Huiqin
AU - Liu, Hai Kun
AU - Sahm, Felix
AU - Capper, David
AU - Bunt, Jens
AU - Richards, Linda J.
AU - Jones, David T.W.
AU - Korshunov, Andrey
AU - Chavez, Lukas
AU - Lichter, Peter
AU - Hoshino, Mikio
AU - Pfister, Stefan M.
AU - Kool, Marcel
AU - Li, Wei
AU - Kawauchi, Daisuke
N1 - Funding Information:
This work was supported by the CERN Research Fellowship (to K.W.P.), the ICGC PedBrain Tumour Project funded by the German Cancer Aid (109252) and the German Federal Ministry of Education and Research (to P.L. and S.M.P.), the KIKA grant (#90) (to M.K.). the U.S. National Institutes of Health Grant K22 5K22CA190440 (to W.L.), the Four Diamonds Fund for Pediatric Cancer Research (to W.L.), and the Deutsche Forschungsgemeinschaft, KA 4472/1-1 (to D.K.). We thank Y. Takahashi (Kyoto University) and K. Kawakami (National Institute of Genetics, Japan) for Tol2 transposon related vectors; Lena Kutscher (DKFZ) for a proof-reading and editing; J. LoTurco (University of Conneticut) for pPB-eGFP vector; R. Gronostajski (State University of New York at Buffalo) for Nfia-En cDNA; D.J. Pan (UT Southwestern Medical Center) and F. Giancotti (MD Anderson Cancer Center) for vectors expressing MST2, Lats and Sav1, K. Reifenberg and K. Dell for helpful assistance for animal experiments at DKFZ; the Imaging and Cytometry, Genomics and Proteomics Core Facilities of the DKFZ and Penn State College of Medicine, and the Carl Zeiss Imaging Center in the DKFZ.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
AB - YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
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U2 - 10.1038/s41467-019-11884-5
DO - 10.1038/s41467-019-11884-5
M3 - Article
C2 - 31477715
AN - SCOPUS:85071773783
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3914
ER -