Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
Oncogene. 2018 Oct;37(40):5451-5465. doi: 10.1038/s41388-018-0326-9. Epub 2018 Jun 7.
Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, MYCN inhibitors have yet to be developed. Here, by integrating evidence from a whole-genome shRNA library screen and the computational inference of master regulator proteins, we identify transcription factor activating protein 4 (TFAP4) as a critical effector of MYCN amplification in neuroblastoma, providing a novel synthetic lethal target. We demonstrate that TFAP4 is a direct target of MYCN in neuroblastoma cells, and that its expression and activity strongly negatively correlate with neuroblastoma patient survival. Silencing TFAP4 selectively inhibits MYCN-amplified neuroblastoma cell growth both in vitro and in vivo, in xenograft mouse models. Mechanistically, silencing TFAP4 induces neuroblastoma differentiation, as evidenced by increased neurite outgrowth and upregulation of neuronal markers. Taken together, our results demonstrate that TFAP4 is a key regulator of MYCN-amplified neuroblastoma and may represent a valuable novel therapeutic target.
尽管已经确定 MYCN 扩增是神经母细胞瘤的不良预后标志物，但尚未开发出 MYCN 抑制剂。在这里，我们通过整合全基因组 shRNA 文库筛选和主调控蛋白的计算推断证据，确定转录因子激活蛋白 4（TFAP4）是神经母细胞瘤中 MYCN 扩增的关键效应因子，为神经母细胞瘤提供了一个新的合成致死靶点。我们证明 TFAP4 是神经母细胞瘤细胞中 MYCN 的直接靶标，其表达和活性与神经母细胞瘤患者的生存强烈负相关。沉默 TFAP4 可选择性地抑制体外和体内 MYCN 扩增神经母细胞瘤细胞的生长，在异种移植小鼠模型中也是如此。从机制上讲，沉默 TFAP4 诱导神经母细胞瘤分化，表现为神经突生长增加和神经元标志物上调。总之，我们的研究结果表明 TFAP4 是 MYCN 扩增神经母细胞瘤的关键调节因子，可能代表一个有价值的新的治疗靶点。
