Neurogenic differentiation factor 1 promotes colorectal cancer cell proliferation and tumorigenesis by suppressing the p53/p21 axis

• Published in: Cancer science Vol. 111; no. 1; pp. 175 - 185
• Main Authors: Lei, Ke, Li, Wenfang, Huang, Can, Li, Yanjun, Alfason, Leader, Zhao, Hezhao, Miyagishi, Makoto, Wu, Shourong, Kasim, Vivi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.01.2020; John Wiley and Sons Inc
• Subjects: Basic Helix-Loop-Helix Transcription Factors - genetics; Beta2 protein; Binding sites; Cancer; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell cycle; Cell Cycle - genetics; Cell growth; Cell Line, Tumor; Cell Proliferation; Chromatin; Cloning; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Deoxyribonucleic acid; DNA; Experiments; Gene Expression Regulation, Neoplastic - genetics; Gene regulation; Genes; HCT116 Cells; Hospitals; Humans; Immunoprecipitation; Kinases; Medulloblastoma; Mortality; Mutagenesis; Neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - pathology; neurogenic differentiation factor 1; Original; p21; p53; p53 Protein; Point mutation; Promoter Regions, Genetic - genetics; Proteins; Regulation; Statistical analysis; Transcription factors; Transcription Factors - genetics; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors; Xenografts; colorectal cancer; cell proliferation; neurogenic differentiation factor 1; p21; p53
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14233

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. In this study, we found that NeuroD1 is a novel negative regulator of tumor suppressor p53 and is highly expressed in colorectal cancer. NeuroD1 binds to p53 promoter and suppresses its transcriptional activity, leading to the inhibition of the p53/p21 axis. NeuroD1‐silencing increases p53 and p21 levels, resulting in an inhibition of colorectal cancer cell proliferation and tumorigenesis potential.