EBF3 reactivation by inhibiting the EGR1/EZH2/HDAC9 complex promotes metastasis via transcriptionally enhancing vimentin in nasopharyngeal carcinoma

• Published in: Cancer letters 2022-02, Vol.527, p.49-65
• Main Authors: Ding, Shirong, Wang, Xin, Lv, Dongming, Tao, Yalan, Liu, Songran, Chen, Chen, Huang, Zilu, Zheng, Shuohan, Wei, Yinghong, Kang, Tiebang, Xia, Yunfei
• Format: Article
• Language: English
• Subjects: Antibodies; Cancer; Cell cycle; Cloning; Early B-cell factor; Early B-Cell factor 3; Early growth response 1; EGR-1 protein; Enhancer of Zeste Homolog 2 Protein - metabolism; Epithelial-mesenchymal transition; Humans; Lymphocytes B; Male; Metastases; Metastasis; Molecular modelling; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - genetics; Neoplasm Metastasis; Patients; Proteins; Throat cancer; Transcription; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Tumor metastasis; Vimentin; Vimentin - pharmacology; Vimentin - therapeutic use
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.12.010

Metastasis is the major reason for treatment failure and accounts for cancer-related death in patients with nasopharyngeal carcinoma. However, the genetic alterations and molecular mechanisms that cause nasopharyngeal carcinoma metastasis are elusive. Herein, we performed RNA sequencing in patients with or without metastasis, and found that the early B-cell factor 3 (EBF3) was significantly elevated in the samples with metastasis. Mechanistically, EBF3 promoted metastasis by directly combining with the promoter of Vimentin and transcriptionally upregulating it. In addition, EBF3 was epigenetically silenced by EGR1/EZH2/HDAC9 complexes via sustaining the high level of H3K27–Me3 at its promoter. Clinically, there was a positive correlation between EBF3 and Vimentin in nasopharyngeal carcinoma tissues. Moreover, high expression of EBF3 or Vimentin was correlated with poor overall survival, while the combination of high EBF3 and Vimentin expression was associated with more significant poor prognosis. Therefore, specific agents targeting EBF3 or stabilizing the EGR1/EZH2/HDAC9 complex could be novel therapeutic strategies for cancer metastasis. •EBF3 is significantly upregulated in metastatic NPC patients with poor survival.•EBF3 promotes NPC cell migration, invasion, and metastasis via Vimentin.•EBF3 is silenced by EGR1/EZH2/HDAC9 complex via histone modification.