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Nat Commun. 2019 Sep 2;10(1):3914. doi: 10.1038/s41467-019-11884-5.

YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.

Author information

1
Hopp-Children's Cancer Center Heidelberg (KiTZ), 69120, Heidelberg, Germany.
2
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
3
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
4
Division of Pediatric Hematology and Oncology, Department of Pediatrics, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, 17033, USA.
5
Department of Biochemistry and Molecular Biology, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, 17033, USA.
6
Department of Pharmacology, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, 17033, USA.
7
Department of Neuropathology, Ste. Anne Hospital, 75014, Paris, France.
8
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
9
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
10
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
11
Department of Neuropathology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
12
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Australia.
14
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
15
Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
16
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
17
Division of Pediatric Hematology and Oncology, Department of Pediatrics, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, 17033, USA. weili@pennstatehealth.psu.edu.
18
Department of Biochemistry and Molecular Biology, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, 17033, USA. weili@pennstatehealth.psu.edu.
19
Hopp-Children's Cancer Center Heidelberg (KiTZ), 69120, Heidelberg, Germany. d.kawauchi@kitz-heidelberg.de.
20
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. d.kawauchi@kitz-heidelberg.de.

Abstract

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.

PMID:
31477715
PMCID:
PMC6718408
DOI:
10.1038/s41467-019-11884-5
[Indexed for MEDLINE]
Free PMC Article

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