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

Guihua Wang,Feng Xu,Junbo Hu,Fuqing Hu,Jing Wang,Yinjia Fu,Xuelai Luo,Jinqing Lan,Xi Yang

doi:10.1038/cddis.2017.1

Abstract

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.

Highlights

Chromatin remodeling is one of the most important mechanisms regulating gene expression
Cell senescence is defined as a state of irreversible proliferative arrest that results in a senescent phenotype, which is characterized by upregulated senescence-associated β-galactosidase (SA-β-gal) activity, cell cycle arrest, formation of senescence-associated heterochromatin foci (SAHF), and inhibited cell proliferation.[13,16]
Cellular senescence is characterized by upregulated SA-β-gal activity, inhibited cell proliferation, cell cycle arrest, and formation of SAHF.[13]

Summary

Introduction

Chromatin remodeling is one of the most important mechanisms regulating gene expression. The mammalian switch/sucrose nonfermentable (SWI/SNF) complex mediates the ATPdependent chromatin remodeling and interacts with various transcriptional co-factors to manipulate gene expression.[1,2] Brahma-related gene-1 (BRG1) is a central subunit of the SWI/ SNF complex that features ATPase activity involved in DNA repair, differentiation, and organ development.[3,4] BRG1 was reported as a tumor suppressor.[5] BRG1 knockdown (KD) promoted tumor metastasis in colorectal cancer (CRC) via the miR-550/RNF43 pathway, indicating that BRG1 is a potential tumor suppressor.[6] the role of BRG1 in cell senescence and proliferation remains controversial. We show that the expression level of BRG1 is inversely correlated with p21, and the KD of BRG1 promotes cellular senescence by increasing the SA-β-gal activity, inhibiting cell proliferation, inducing cell cycle arrest, and forming SAHF. BRG1 KD cells resulted in smaller tumor formation than that of control cells in vivo

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Results

Conclusion