Cargando…

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

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. Th...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Zijun, Li, Xiaoming, Liu, Zhiqing, Huang, Lixun, Yao, Yuying, Li, Liuyou, Chen, Jian, Zhang, Rongxin, Zhou, Jia, Wang, Lijing, Zhang, Qian-Qian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381267/
https://www.ncbi.nlm.nih.gov/pubmed/32765266
http://dx.doi.org/10.3389/fphar.2020.01043
_version_ 1783563013282856960
author Zhou, Zijun
Li, Xiaoming
Liu, Zhiqing
Huang, Lixun
Yao, Yuying
Li, Liuyou
Chen, Jian
Zhang, Rongxin
Zhou, Jia
Wang, Lijing
Zhang, Qian-Qian
author_facet Zhou, Zijun
Li, Xiaoming
Liu, Zhiqing
Huang, Lixun
Yao, Yuying
Li, Liuyou
Chen, Jian
Zhang, Rongxin
Zhou, Jia
Wang, Lijing
Zhang, Qian-Qian
author_sort Zhou, Zijun
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7381267
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-73812672020-08-05 A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression Zhou, Zijun Li, Xiaoming Liu, Zhiqing Huang, Lixun Yao, Yuying Li, Liuyou Chen, Jian Zhang, Rongxin Zhou, Jia Wang, Lijing Zhang, Qian-Qian Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2020-07-10 /pmc/articles/PMC7381267/ /pubmed/32765266 http://dx.doi.org/10.3389/fphar.2020.01043 Text en Copyright © 2020 Zhou, Li, Liu, Huang, Yao, Li, Chen, Zhang, Zhou, Wang and Zhang http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhou, Zijun
Li, Xiaoming
Liu, Zhiqing
Huang, Lixun
Yao, Yuying
Li, Liuyou
Chen, Jian
Zhang, Rongxin
Zhou, Jia
Wang, Lijing
Zhang, Qian-Qian
A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression
title A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression
title_full A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression
title_fullStr A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression
title_full_unstemmed A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression
title_short A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression
title_sort bromodomain-containing protein 4 (brd4) inhibitor suppresses angiogenesis by regulating ap-1 expression
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381267/
https://www.ncbi.nlm.nih.gov/pubmed/32765266
http://dx.doi.org/10.3389/fphar.2020.01043
work_keys_str_mv AT zhouzijun abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT lixiaoming abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT liuzhiqing abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT huanglixun abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT yaoyuying abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT liliuyou abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT chenjian abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT zhangrongxin abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT zhoujia abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT wanglijing abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT zhangqianqian abromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT zhouzijun bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT lixiaoming bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT liuzhiqing bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT huanglixun bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT yaoyuying bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT liliuyou bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT chenjian bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT zhangrongxin bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT zhoujia bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT wanglijing bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression
AT zhangqianqian bromodomaincontainingprotein4brd4inhibitorsuppressesangiogenesisbyregulatingap1expression