Unknown

Dataset Information

0

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 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.

SUBMITTER: Veschi V 

PROVIDER: S-EPMC5233415 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications


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<sup>K20me1</sup> methyltransferase, as a dru  ...[more]

Similar Datasets

2017-01-09 | GSE81626 | GEO
| S-EPMC6485357 | biostudies-literature
| S-EPMC7493834 | biostudies-literature
| S-EPMC7766894 | biostudies-literature
| S-EPMC5506440 | biostudies-literature
| S-EPMC3361704 | biostudies-literature
| S-EPMC10168247 | biostudies-literature
| S-SCDT-10_1038-S44320-024-00032-X | biostudies-other
| S-EPMC528723 | biostudies-literature
| S-EPMC8175350 | biostudies-literature