Ubiquitination of NOTCH2 by DTX3 suppresses the proliferation and migration of human esophageal carcinoma

• Published in: Cancer science Vol. 111; no. 2; pp. 489 - 501
• Main Authors: Ding, Xin‐Yu, Hu, Hai‐Yang, Huang, Ke‐Nan, Wei, Rong‐Qiang, Min, Jie, Qi, Chen, Tang, Hua, Qin, Xiong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2020; John Wiley and Sons Inc
• Subjects: Animals; anti–oncogene; Biodegradation; Cancer therapies; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Disease Progression; DTX3; Epithelial cells; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immunoglobulins; Laboratory animals; Male; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Transplantation; NOTCH2; Notch2 protein; Original; Plasmids; Proteins; Proteolysis; Receptor, Notch2 - chemistry; Receptor, Notch2 - metabolism; Signal Transduction; Therapeutic applications; Tumor cell lines; Tumorigenicity; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; China; NOTCH2; DTX3; esophageal carcinoma; anti-oncogene; ubiquitination
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14288

The NOTCH2 gene plays a role in the development of many tumors. Deltex E3 ubiquitin ligase 3 (DTX3) was identified as a novel E3 ligase for NOTCH2 and as a potential therapeutic target for esophageal cancer. However, whether DTX3 could regulate NOTCH2 to suppress the progression of esophageal carcinoma remains unknown. In our study, NOTCH2 had higher expression in human esophageal carcinoma cell lines compared to normal human esophageal epithelial cell line, and ablation of NOTCH2 suppressed the proliferation and migration of esophageal carcinoma cells. A novel E3 ligase for NOTCH2 was identified by yeast two‐hybrid (Y2H) screening, and DTX3 promoted the ubiquitination and degradation of NOTCH2. Further study showed that DTX3 overexpression suppressed the proliferation and tumorigenicity of human oesophageal carcinoma cells. The analysis of tissue samples from patients revealed that the expression of NOTCH2 was high while the expression of DTX3 was low in esophageal cancer. Furthermore, the expression of DTX3 and NOTCH2 showed a significant negative correlation in human oesophageal cancer samples. Our study suggested that the DTX3‐NOTCH2 axis plays an important role in the progression of esophageal cancer, and DTX3 acts as an anti–oncogene in esophageal carcinoma, potentially offering a therapeutic target for esophageal cancer. The DTX3‐NOTCH2 axis plays an important role in the progression of esophageal cancer, and DTX3 acts as an anti–oncogene in esophageal carcinoma, potentially offering a therapeutic target for esophageal cancer.