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BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis
Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstra...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833665/ https://www.ncbi.nlm.nih.gov/pubmed/29434197 http://dx.doi.org/10.1038/s41419-017-0181-6 |
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author | Dong, Xingchen Hu, Xiangming Chen, Jinjing Hu, Dan Chen, Lin-Feng |
author_facet | Dong, Xingchen Hu, Xiangming Chen, Jinjing Hu, Dan Chen, Lin-Feng |
author_sort | Dong, Xingchen |
collection | PubMed |
description | Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3′-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs. |
format | Online Article Text |
id | pubmed-5833665 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58336652018-03-05 BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis Dong, Xingchen Hu, Xiangming Chen, Jinjing Hu, Dan Chen, Lin-Feng Cell Death Dis Article Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3′-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs. Nature Publishing Group UK 2018-02-12 /pmc/articles/PMC5833665/ /pubmed/29434197 http://dx.doi.org/10.1038/s41419-017-0181-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dong, Xingchen Hu, Xiangming Chen, Jinjing Hu, Dan Chen, Lin-Feng BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis |
title | BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis |
title_full | BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis |
title_fullStr | BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis |
title_full_unstemmed | BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis |
title_short | BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis |
title_sort | brd4 regulates cellular senescence in gastric cancer cells via e2f/mir-106b/p21 axis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833665/ https://www.ncbi.nlm.nih.gov/pubmed/29434197 http://dx.doi.org/10.1038/s41419-017-0181-6 |
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