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

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

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.

MeSH terms

  • Cell Differentiation
  • Cell Proliferation
  • Epigenesis, Genetic*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / physiology
  • Humans
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology
  • Quinazolines / pharmacology
  • RNA, Small Interfering / genetics*
  • Tumor Suppressor Protein p53 / analysis
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • 6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine
  • Quinazolines
  • RNA, Small Interfering
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Histone-Lysine N-Methyltransferase
  • KMT5A protein, human