Journal
CANCER CELL
Volume 31, Issue 1, Pages 50-63Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.12.002
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Funding
- St. Baldrick's Foundation
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through the Ontario Genomics Institute
- Innovative Medicines Initiative (EU/EFPIA) [115766]
- Janssen
- Merck
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- AIRC [IG17734]
- MIUR PRIN
- Center for Cancer Research, NCI, as part of the Intramural Research Program, NIH
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Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4(K20me1) methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53(K382me1) leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB.
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