NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma
NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma
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NeuroD1 决定髓母细胞瘤中肿瘤细胞的分化
DOI：
10.1016/j.celrep.2020.107782
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发表时间：
2020-06-23
期刊：
影响因子：
8.8
通讯作者：
Yang, Zeng-jie
中科院分区：
文献类型：
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作者：
Cheng, Yan;Liao, Shengyou;Yang, Zeng-jie
肿瘤细胞具有无限增殖和分化紊乱的特点。使用单细胞RNA测序，我们证明髓母细胞瘤（MB）中的肿瘤细胞以类似于其正常起源细胞小脑颗粒神经元前体的方式保持其分化能力。MB细胞一旦分化，就会永久失去增殖能力和致瘤潜能。分化的MB细胞高度表达一种螺旋-环-螺旋转录因子NeuroD1，强迫表达NeuroD1促进MB细胞分化。组蛋白3赖氨酸-27 （H3K27me3）的三甲基化可抑制大块MB细胞中NeuroD1的表达。抑制组蛋白赖氨酸甲基转移酶EZH2可阻止H3K27三甲基化，导致MB细胞中NeuroD1表达增加，分化增强，从而降低肿瘤生长。这些研究揭示了MB细胞分化的机制，并为通过刺激肿瘤细胞分化治疗MB（潜在的其他恶性肿瘤）提供了依据。
Tumor cells are characterized by unlimited proliferation and perturbed differentiation. Using single-cell RNA sequencing, we demonstrate that tumor cells in medulloblastoma (MB) retain their capacity to differentiate in a similar way as their normal originating cells, cerebellar granule neuron precursors. Once they differentiate, MB cells permanently lose their proliferative capacity and tumorigenic potential. Differentiated MB cells highly express NeuroD1, a helix-loop-helix transcription factor, and forced expression of NeuroD1 promotes the differentiation of MB cells. The expression of NeuroD1 in bulk MB cells is repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced differentiation in MB cells, which consequently reduces tumor growth. These studies reveal the mechanisms underlying MB cell differentiation and provide rationales to treat MB (potentially other malignancies) by stimulating tumor cell differentiation.