Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression

Reisman, David; Strobeck, Matthew W.; Betz, Bryan L.; Sciariotta, Janiece; Funkhouser, William K.; Murchardt, Christian; Yaniv, Moshe; Sherman, Larry S.; Knudsen, Erik S.; Weissman, Bernard E.

doi:10.1038/sj.onc.1205188

Cited by 140 publications

(188 citation statements)

References 68 publications

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“…The BRM gene in BRG1/BRM-deficient cell lines is not mutated We and others have noted that BRG1 and BRM protein levels are consistently lost together in a variety of cancer cell lines (Muchardt and Yaniv, 2001;Reisman et al, 2002). BRG1 has been found to be mutated (Wong et al, 2000)) in these cell lines, but the various mechanisms that might underlie BRM loss have not been elucidated.…”

Section: Resultsmentioning

confidence: 98%

“…To confirm that endogenous BRM is functionally reconstituted by transient HDAC inhibitor exposure, we asked if these HDAC inhibitors could induce the expression of CD44, a BRM-dependent gene (Strobeck et al, 2001;Reisman et al, 2002). CD44 expression was not detectable in butyrate-treated cells (Figure 4a).…”

Section: Reexpression Of Endogenous Brm By Hdac Inhibitors Restored Cmentioning

confidence: 99%

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The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

et al. 2007

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The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRMrelated gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.

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Section: Resultsmentioning

confidence: 98%

Section: Reexpression Of Endogenous Brm By Hdac Inhibitors Restored Cmentioning

confidence: 99%

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

et al. 2007

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“…Other more distantly related enzymes include human hBrm, Brg1 and the CHD family (CHD1-7). Of note, human hBrm and Brg1 are two candidate tumor suppressor genes that are implicated in repression of E2F target genes and induction of cell differentiation and senescence, through physical and functional interactions with the pRB protein (33,38,56,76,85,104,105,115,124,134,142). Since E2F target genes are incorporated into SAHF and formation of SAHF requires an intact pRB pathway (88,140), hBrm and/or Brg1 might be involved in SAHF assembly, perhaps through deposition of macroH2A.…”

Section: Incorporation Of Other Sahf Componentsmentioning

confidence: 99%

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

Adams

2007

Gene

161

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Cellular senescence is an important tumor suppression process, and a possible contributor to tissue aging. Senescence is accompanied extensive changes in chromatin structure. In particular, many senescent cells accumulate specialized domains of facultative heterochromatin, called Senescence Associated Heterochromatin Foci (SAHF), which are thought to repress expression of proliferationpromoting genes, thereby contributing to senescence-associated proliferation arrest. This article reviews our current understanding of the structure, assembly and function of these SAHF at a cellular level. The possible contribution of SAHF to tumor suppression and tissue aging is also critically discussed.

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“…Complexes containing BRG1 have been shown to be required for cell cycle control, apoptosis and differentiation in several biological systems (Dunaief et al, 1994;Murphy et al, 1999;Bultman et al, 2000;Reisman et al, 2002;Martens and Winston, 2003;Hendricks et al, 2004;de la Serna et al, 2006). Homozygous knockout mice for the Brg1 gene die during the embryonic stage, whereas heterozygotic survivors are prone to tumors (Bultman et al, 2000;Saha et al, 2006;de la Serna et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Homozygous knockout mice for the Brg1 gene die during the embryonic stage, whereas heterozygotic survivors are prone to tumors (Bultman et al, 2000;Saha et al, 2006;de la Serna et al, 2006). BRG1 protein can interact with different proteins involved in regulation of transcription, such as factors involved in myeloid, erythrocyte, lymphocyte, muscle, neural and adipocyte commitment and/or differentiation (Dunaief et al, 1994;Murphy et al, 1999;Bultman et al, 2000;Reisman et al, 2002;Martens and Winston, 2003;Hendricks et al, 2004;Saha et al, 2006;de la Serna et al, 2006). The BRG1 chromatin remodeling protein can associate with numerous chromatin-modifying complexes, including transcription co-activators and corepressors.…”

Section: Introductionmentioning

confidence: 99%

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

et al. 2010

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We focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130-and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology.

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Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression

Cited by 140 publications

References 68 publications

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

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