A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression

Zijun Zhou, Xiaoming Li, Zhiqing Liu, Lixun Huang, Yuying Yao, Liuyou Li, Jian Chen, Rongxin Zhang, Jia Zhou, Lijing Wang, Qian Qian Zhang

Research output: Contribution to journalArticle

Abstract

Angiogenesis dysregulation contributes to inflammation, infections, immune disorders, and carcinogenesis. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader that recognizes histone proteins and acts as a transcriptional regulator to trigger tumor growth and the inflammatory response. The pan-bromodomain and extra-terminal domain (BET) inhibitor, (+)-JQ1 (1), was reported to inhibit angiogenesis. However, owing to the non-selectivity action of (+)-JQ1 towards all BET family members, the role of BRD4 and that of its bromodomains (BD1 and BD2) in angiogenesis remains elusive. Herein, we identified a potent BRD4 inhibitor, ZL0513 (7), which exhibited significant anti-angiogenic effects in chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. This inhibitor also directly suppressed the viability and tube formation of human umbilical vascular endothelial cells (HUVECs). Moreover, ZL0513 (7) was found to inhibit the phosphorylation of c-jun and c-fos, important members of activating protein-1 (AP-1) transcription factor complexes that enhance angiogenesis. The findings on this novel BRD4 inhibitor indicate that, in addition to being a powerful pharmacological tool for further elucidating the roles and functions of BRD4 and its BD domains in angiogenesis, it may serve as a potential therapeutic strategy for targeting the vasculature in various angiogenesis-dysregulated human diseases.

Original languageEnglish (US)
Article number1043
JournalFrontiers in Pharmacology
Volume11
DOIs
StatePublished - Jul 10 2020

Keywords

  • AP-1 transcription factors
  • BD domains
  • BRD4 inhibitors
  • angiogenesis
  • bromodomain-containing protein 4 (BRD4)

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Zhou, Z., Li, X., Liu, Z., Huang, L., Yao, Y., Li, L., Chen, J., Zhang, R., Zhou, J., Wang, L., & Zhang, Q. Q. (2020). A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression. Frontiers in Pharmacology, 11, [1043]. https://doi.org/10.3389/fphar.2020.01043