Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.
Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.
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DOI：
10.1158/1541-7786.mcr-20-0693
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发表时间：
2020-12
期刊：
影响因子：
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通讯作者：
Philpott A
中科院分区：
文献类型：
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作者：
Ali FR;Marcos D;Chernukhin I;Woods LM;Parkinson LM;Wylie LA;Papkovskaia TD;Davies JD;Carroll JS;Philpott A
儿童癌症通常类似于被困的发育中间状态，不能参与正常的分化程序，典型的是来自发育中的交感神经系统的高风险神经母细胞瘤。神经母细胞瘤细胞类似于被一个稳定但异常的表观遗传程序所困住的神经母细胞，该程序是由一个核心发育调节因子转录回路的持续表达以及MYCN或MYC （MYC）的升高所控制的。转录因子ASCL1是神经母细胞瘤的关键主调控因子，在其他几种肿瘤类型中具有致癌和肿瘤抑制活性。使用功能突变方法，我们发现阻止神经母细胞瘤细胞中cdk依赖性ASCL1的磷酸化可以协同抑制myc驱动的支持神经母细胞身份和增殖的核心回路，同时激活驱动有丝分裂退出和神经元分化的持久基因程序。
Paediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation programme, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberant epigenetic programme controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (MYC). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumour suppressive activities in several other tumour types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives co-ordinated suppression of the MYC-driven core circuit supporting neuroblast identity and proliferation, while simultaneously activating an enduring gene programme driving mitotic exit and neuronal differentiation.