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

Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Veronica Veschi, Zhihui Liu, Ty C. Voss, Laurent Ozbun, Berkley Gryder, Chunhua Yan, Ying Hu, Anqi Ma, Jian Jin, Sharlyn J. Mazur, Norris Lam, Barbara K. Souza, Giuseppe Giannini, Gordon L. Hager, Cheryl H. Arrowsmith, Javed Khan, Ettore Appella, Carol J. Thiele
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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Teaser

Veschi et al. perform both genetic and chemical screening to identify histone methyltransferase SETD8 as a potential target in neuroblastoma (NB). Chemical or genetic inhibition of SETD8 in NB leads to increased p53 activity and reduced tumor cell growth, resulting in prolonged survival in mouse models of NB.


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