The E3 ligase NEURL3 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma by promoting vimentin degradation

• Published in: Journal of experimental & clinical cancer research Vol. 43; no. 1; pp. 14 - 16
• Main Authors: Zhou, Shi-Qing, Feng, Ping, Ye, Ming-Liang, Huang, Sheng-Yan, He, Shi-Wei, Zhu, Xun-Hua, Chen, Jun, Zhang, Qun, Li, Ying-Qing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.01.2024; BioMed Central; BMC
• Subjects: Antibodies; Cancer; Cancer therapies; Carcinoma; Cells; Datasets; DNA methylation; Epithelial-Mesenchymal Transition; Genomes; Health aspects; Humans; Immunohistochemistry; Ligases; Metastasis; Methylation; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Neoplasms - genetics; NEURL3; Plasmids; Proteins; Stem cells; Throat cancer; Tumorigenesis; Ubiquitin; Ubiquitin-Protein Ligases - genetics; Vimentin; Vimentin - genetics; Wound healing; China; United States > US; Nasopharyngeal carcinoma; Vimentin; DNA methylation; Metastasis; NEURL3
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-024-02945-9

Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to the initiation and progression of NPC. However, the precise regulatory mechanism behind these processes remains poorly understood. Bisulfite pyrosequencing, RT-qPCR, western blot, and immunohistochemistry were used to test the methylation and expression level of NEURL3 and its clinical significance. The biological function of NEURL3 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of NEURL3. The promoter region of NEURL3, encoding an E3 ubiquitin ligase, was obviously hypermethylated, leading to its downregulated expression in NPC. Clinically, NPC patients with a low NEURL3 expression indicated an unfavorable prognosis and were prone to develop distant metastasis. Overexpression of NEURL3 could suppress the epithelial mesenchymal transition and metastasis of NPC cells in vitro and in vivo. Mechanistically, NEURL3 promoted Vimentin degradation by increasing its K48-linked polyubiquitination at lysine 97. Specifically, the restoration of Vimentin expression could fully reverse the tumor suppressive effect of NEURL3 overexpression in NPC cells. Collectively, our study uncovers a novel mechanism by which NEURL3 inhibits NPC metastasis, thereby providing a promising therapeutic target for NPC treatment.