YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Brain Neoplasms
/ genetics
Carcinogenesis
/ genetics
Cell Line, Tumor
Cell Transformation, Neoplastic
/ genetics
DNA-Binding Proteins
/ genetics
Ependymoma
/ genetics
HEK293 Cells
Humans
Mice
NFI Transcription Factors
/ genetics
NIH 3T3 Cells
Neural Stem Cells
/ metabolism
Nuclear Proteins
/ genetics
Oncogene Proteins, Fusion
/ genetics
Phosphoproteins
/ genetics
Transcription Factors
/ genetics
YAP-Signaling Proteins
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 09 2019
02 09 2019
Historique:
received:
08
01
2019
accepted:
07
08
2019
entrez:
4
9
2019
pubmed:
4
9
2019
medline:
31
12
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31477715
doi: 10.1038/s41467-019-11884-5
pii: 10.1038/s41467-019-11884-5
pmc: PMC6718408
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
DNA-Binding Proteins
0
MAMLD1 protein, human
0
NFI Transcription Factors
0
Nuclear Proteins
0
Oncogene Proteins, Fusion
0
Phosphoproteins
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3914Subventions
Organisme : NCI NIH HHS
ID : K22 CA190440
Pays : United States
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