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Cancer Cell. 2017 Jan 9;31(1):50-63. doi: 10.1016/j.ccell.2016.12.002.

Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma.

Author information

1
Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, CRC, 1-3940, 10 Center Drive MSC-1105, Bethesda, MD 20892, USA.
2
High-Throughput Imaging Facility, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
3
Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
4
Center for Biomedical Informatics and Information Technology, Center for Cancer Research, National Cancer Institute, Rockville, MD 20850, USA.
5
Department of Structural and Chemical Biology, Oncological Sciences, Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Chemical Immunology Section, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA.
7
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
8
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
9
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
10
Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, CRC, 1-3940, 10 Center Drive MSC-1105, Bethesda, MD 20892, USA. Electronic address: ct47a@nih.gov.

Abstract

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 H4K20me1 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 p53K382me1, 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.

KEYWORDS:

SETD8; differentiation; epigenetics; neuroblastoma; p53; siRNA screen

PMID:
28073004
PMCID:
PMC5233415
DOI:
10.1016/j.ccell.2016.12.002
[Indexed for MEDLINE]
Free PMC Article

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