title: Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma.
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 H4K20me1methyltransferase, 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.
authors.affiliation: 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.
authors.forename: Veronica
authors.initials: V
authors.lastname: Veschi
authors.affiliation: 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.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Liu
authors.affiliation: High-Throughput Imaging Facility, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Ty C
authors.initials: TC
authors.lastname: Voss
authors.affiliation: High-Throughput Imaging Facility, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ozbun
authors.affiliation: Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Berkley
authors.initials: B
authors.lastname: Gryder
authors.affiliation: Center for Biomedical Informatics and Information Technology, Center for Cancer Research, National Cancer Institute, Rockville, MD 20850, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yan
authors.affiliation: Center for Biomedical Informatics and Information Technology, Center for Cancer Research, National Cancer Institute, Rockville, MD 20850, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Structural and Chemical Biology, Oncological Sciences, Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Anqi
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Structural and Chemical Biology, Oncological Sciences, Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Chemical Immunology Section, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Sharlyn J
authors.initials: SJ
authors.lastname: Mazur
authors.affiliation: 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.
authors.forename: Norris
authors.initials: N
authors.lastname: Lam
authors.affiliation: 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.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Souza
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Chemical Immunology Section, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.affiliation: 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.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*
chemical_list: C000595015:6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine; D011799:Quinazolines; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human
keywords: SETD8; differentiation; epigenetics; neuroblastoma; p53; siRNA screen