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

Abstract

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.

• Authors: Ke Lei, Wenfang Li, Can Huang, Yanjun Li, Leader Alfason, Hezhao Zhao, Makoto Miyagishi, Shourong Wu, Vivi Kasim
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 1 Pg. 175-185 (Jan 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 31715070 (Publication Type: Journal Article)
• Copyright: © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Cyclin-Dependent Kinase Inhibitor p21
• NEUROD1 protein, human
• TP53 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53

Topics

• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Carcinogenesis (genetics, pathology)
• Cell Cycle (genetics)
• Cell Line, Tumor
• Cell Proliferation
• Colorectal Neoplasms (genetics, pathology)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• HCT116 Cells
• Humans
• Neuroblastoma (genetics, pathology)
• Promoter Regions, Genetic (genetics)
• Transcription Factors (genetics)
• Tumor Suppressor Protein p53 (genetics)