Veschi Veronica, Liu Zhihui, Voss Ty C, Ozbun Laurent, Gryder Berkley, Yan Chunhua, Hu Ying, Ma Anqi, Jin Jian, Mazur Sharlyn J, Lam Norris, Souza Barbara K, Giannini Giuseppe, Hager Gordon L, Arrowsmith Cheryl H, Khan Javed, Appella Ettore, Thiele Carol J
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.
High-Throughput Imaging Facility, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Cancer Cell. 2017 Jan 9;31(1):50-63. doi: 10.1016/j.ccell.2016.12.002.
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 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, 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.
鉴于高危神经母细胞瘤（NB）中可成药突变的匮乏，我们开展了以染色质为重点的小干扰RNA和化学筛选，以发现对高危NB分化阻滞至关重要的表观遗传调节因子。高内涵Opera成像鉴定出53个基因，其表达缺失导致NB细胞增殖减少，其中16个还诱导了分化。从中，二次化学筛选确定H4甲基转移酶SETD8为可成药的NB靶点。功能研究表明，SETD8缺失通过降低p53挽救了p53的促凋亡和细胞周期阻滞功能，从而导致p53经典途径的激活。在临床前异种移植NB模型中，基因或药理学（UNC0379）抑制SETD8赋予了显著的生存优势，为SETD8作为NB的治疗靶点提供了证据。
