Neurogenic differentiation factor 1 promotes colorectal cancer cell proliferation and tumorigenesis by suppressing the p53/p21 axis
Neurogenic differentiation factor 1 promotes colorectal cancer cell proliferation and tumorigenesis by suppressing the p53/p21 axis
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神经源性分化因子 1 通过抑制 p53/p21 轴促进结直肠癌细胞增殖和肿瘤发生
DOI：
10.1111/cas.14233
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发表时间：
2019-12-10
期刊：
影响因子：
5.7
通讯作者：
Kasim, Vivi
中科院分区：
文献类型：
--
作者：
Lei, Ke;Li, Wenfang;Kasim, Vivi
神经源性分化因子1（NeuroD 1）是促进神经元分化和成熟的关键转录因子。NeuroD 1与神经母细胞瘤和髓母细胞瘤有关，但其促进肿瘤发生的分子机制尚不清楚。此外，NeuroD 1在非神经恶性肿瘤中的作用尚未得到广泛表征。在这里，我们发现NeuroD 1在结直肠癌中高度表达。NeuroD 1沉默诱导p21的表达，p21是细胞周期的主要调节因子，导致G2-M期阻滞和结直肠癌细胞增殖以及集落形成潜力的抑制。此外，NeuroD 1介导的p21表达调节以p53依赖性方式发生。通过染色质免疫沉淀和p53启动子的预测NeuroD 1结合位点的点突变分析，我们发现NeuroD 1直接结合p53启动子并抑制其转录，导致NeuroD 1沉默的结直肠癌细胞中p53表达增加。最后，异种移植实验表明，NeuroD 1沉默通过调节p53表达来抑制结直肠癌细胞的肿瘤发生潜力。这些发现揭示了NeuroD 1作为p53/p21轴的新型调节剂，强调了其在促进非神经恶性肿瘤中的重要性。此外，这项研究提供了深入了解p53的转录调控。
Neurogenic differentiation factor 1 (NeuroD1) is a transcription factor critical for promoting neuronal differentiation and maturation. NeuroD1 is involved in neuroblastoma and medulloblastoma; however, its molecular mechanism in promoting tumorigenesis remains unclear. Furthermore, the role of NeuroD1 in non–neural malignancies has not been widely characterized. Here, we found that NeuroD1 is highly expressed in colorectal cancer. NeuroD1‐silencing induces the expression of p21, a master regulator of the cell cycle, leading to G2‐M phase arrest and suppression of colorectal cancer cell proliferation as well as colony formation potential. Moreover, NeuroD1‐mediated regulation of p21 expression occurs in a p53‐dependent manner. Through chromatin immunoprecipitation and point mutation analysis in the predicted NeuroD1 binding site of the p53 promoter, we found that NeuroD1 directly binds to the p53 promoter and suppresses its transcription, resulting in increased p53 expression in NeuroD1‐silenced colorectal cancer cells. Finally, xenograft experiments demonstrated that NeuroD1‐silencing suppresses colorectal cancer cell tumorigenesis potential by modulating p53 expression. These findings reveal NeuroD1 as a novel regulator of the p53/p21 axis, underscoring its importance in promoting non–neural malignancies. Furthermore, this study provides insight into the transcriptional regulation of p53.