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Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway

Brahma-related gene-1 (BRG1) is the specific ATPase of switch/sucrose nonfermentable chromatin-remodeling complex that is aberrantly expressed or mutated in various cancers. However, the exact role of BRG1 in oncogenesis remains unknown. In this study, we demonstrate that the knockdown (KD) of BRG1...

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Autores principales: Wang, Guihua, Fu, Yinjia, Hu, Fuqing, Lan, Jinqing, Xu, Feng, Yang, Xi, Luo, Xuelai, Wang, Jing, Hu, Junbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386468/
https://www.ncbi.nlm.nih.gov/pubmed/28182012
http://dx.doi.org/10.1038/cddis.2017.1
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author Wang, Guihua
Fu, Yinjia
Hu, Fuqing
Lan, Jinqing
Xu, Feng
Yang, Xi
Luo, Xuelai
Wang, Jing
Hu, Junbo
author_facet Wang, Guihua
Fu, Yinjia
Hu, Fuqing
Lan, Jinqing
Xu, Feng
Yang, Xi
Luo, Xuelai
Wang, Jing
Hu, Junbo
author_sort Wang, Guihua
collection PubMed
description Brahma-related gene-1 (BRG1) is the specific ATPase of switch/sucrose nonfermentable chromatin-remodeling complex that is aberrantly expressed or mutated in various cancers. However, the exact role of BRG1 in oncogenesis remains unknown. In this study, we demonstrate that the knockdown (KD) of BRG1 promotes cellular senescence by influencing the SIRT1/p53/p21 signal axis in colorectal cancer (CRC). In particular, we reveal that the expression level of BRG1 is inversely correlated with p21, one of the classic senescence regulators, and is decreased in senescent CRC cells. KD of BRG1 promoting senescence is indicated by the increase of senescence-associated β-galactosidase (SA-β-gal) activity, inhibition of cell proliferation, induction of cell cycle arrest, and formation of senescence-associated heterochromatin foci. BRG1 binds to SIRT1 and interferes with SIRT1-mediated deacetylation of p53 at K382. Rescue experiments by co-silencing p53 or treatment with EX527, a SIRT1-specific inhibitor, abrogated the cellular senescence induced by KD of BRG1. BRG1 KD cells resulted in smaller tumor formation than that in control cells in vivo. Collectively, our study shows that BRG1 has an important role in cellular senescence and tumor growth. The BRG1/SIRT1/p53 signal axis is a novel mechanism of cell senescence in CRC and is a new potential target for cancer therapy.
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spelling pubmed-53864682017-04-26 Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway Wang, Guihua Fu, Yinjia Hu, Fuqing Lan, Jinqing Xu, Feng Yang, Xi Luo, Xuelai Wang, Jing Hu, Junbo Cell Death Dis Original Article Brahma-related gene-1 (BRG1) is the specific ATPase of switch/sucrose nonfermentable chromatin-remodeling complex that is aberrantly expressed or mutated in various cancers. However, the exact role of BRG1 in oncogenesis remains unknown. In this study, we demonstrate that the knockdown (KD) of BRG1 promotes cellular senescence by influencing the SIRT1/p53/p21 signal axis in colorectal cancer (CRC). In particular, we reveal that the expression level of BRG1 is inversely correlated with p21, one of the classic senescence regulators, and is decreased in senescent CRC cells. KD of BRG1 promoting senescence is indicated by the increase of senescence-associated β-galactosidase (SA-β-gal) activity, inhibition of cell proliferation, induction of cell cycle arrest, and formation of senescence-associated heterochromatin foci. BRG1 binds to SIRT1 and interferes with SIRT1-mediated deacetylation of p53 at K382. Rescue experiments by co-silencing p53 or treatment with EX527, a SIRT1-specific inhibitor, abrogated the cellular senescence induced by KD of BRG1. BRG1 KD cells resulted in smaller tumor formation than that in control cells in vivo. Collectively, our study shows that BRG1 has an important role in cellular senescence and tumor growth. The BRG1/SIRT1/p53 signal axis is a novel mechanism of cell senescence in CRC and is a new potential target for cancer therapy. Nature Publishing Group 2017-02 2017-02-09 /pmc/articles/PMC5386468/ /pubmed/28182012 http://dx.doi.org/10.1038/cddis.2017.1 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Wang, Guihua
Fu, Yinjia
Hu, Fuqing
Lan, Jinqing
Xu, Feng
Yang, Xi
Luo, Xuelai
Wang, Jing
Hu, Junbo
Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway
title Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway
title_full Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway
title_fullStr Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway
title_full_unstemmed Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway
title_short Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway
title_sort loss of brg1 induces crc cell senescence by regulating p53/p21 pathway
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386468/
https://www.ncbi.nlm.nih.gov/pubmed/28182012
http://dx.doi.org/10.1038/cddis.2017.1
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