Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation Journal Article


Authors: Fernandez-L, A.; Squatrito, M.; Northcott, P.; Awan, A.; Holland, E. C.; Taylor, M. D.; Nahlé, Z.; Kenney, A. M.
Article Title: Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation
Abstract: Radiation therapy remains the standard of care for many cancers, including the malignant pediatric brain tumor medulloblastoma. Radiation leads to long-term side effects, whereas radioresistance contributes to tumor recurrence. Radio-resistant medulloblastoma cells occupy the perivascular niche. They express Yes-associated protein (YAP), a Sonic hedgehog (Shh) target markedly elevated in Shh-driven medulloblastomas. Here we report that YAP accelerates tumor growth and confers radioresistance, promoting ongoing proliferation after radiation. YAP activity enables cells to enter mitosis with un-repaired DNA through driving insulin-like growth factor 2 (IGF2) expression and Akt activation, resulting in ATM/Chk2 inactivation and abrogation of cell cycle checkpoints. Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in medulloblastoma. © 2012 Macmillan Publishers Limited All rights reserved.
Keywords: cerebellum; dna damage; medulloblastoma; sonic hedgehog; yap; igf
Journal Title: Oncogene
Volume: 31
Issue: 15
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2012-04-12
Start Page: 1923
End Page: 1937
Language: English
DOI: 10.1038/onc.2011.379
PROVIDER: scopus
PUBMED: 21874045
PMCID: PMC3583298
DOI/URL:
Notes: --- - "Export Date: 1 May 2012" - "CODEN: ONCNE" - "Source: Scopus"
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  1. Eric Holland
    225 Holland