PDF(Pubmed)
Abstract：
MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN\'s active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.
摘要：
MYCN激活参与核糖体生物发生的典型MYC靶标，蛋白质合成，并抑制神经元分化基因以驱动神经母细胞瘤（NB）的肿瘤发生。MYCN如何协调全球基因表达仍未完全了解。我们的研究发现，MYCN结合启动子来上调典型的MYC靶标，但同时结合增强子和启动子来抑制分化基因。MYCN结合还增加了典型MYC靶启动子上的H3K4me3和H3K27ac，并减少了神经元分化基因增强子和启动子上的H3K27ac。WDR5促进MYCN启动子结合以激活典型的MYC靶基因，而MYCN招募G9a增强子来抑制神经元分化基因。使用WDR5和G9a抑制剂靶向MYCN的活性和抑制转录活性协同抑制NB生长。我们证明了MYCN与WDR5和G9a合作来协调全局基因转录。这两种辅因子的靶向是间接靶向MYCN的致癌活性的新型治疗策略。
