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

Abstract

Mammalian cells express two homologs of the SWI2 subunit of the SWI/SNF chromatin-remodeling complex called BRG1 and BRM. Whether the SWI/SNF complexes formed by these two subunits perform identical or dierent functions remains an important question. In this report, we show concomitant downregulation of BRG1 and BRM in six human tumor cell lines. This down-regulation occurs at the level of mRNA abundance. We tested whether BRM could aect aberrant cellular functions attributed to BRG1 in tumor cell lines. By transient transfection, we found that BRM can restore RB-mediated cell cycle arrest, induce expression of CD44 protein and suppress Cyclin A expression. Therefore, BRM may be consistently downregulated with BRG1 during neoplastic progression because they share some redundant functions. However, assorted tissues from BRM null/BRG1-positive mice lack CD44 expression, suggesting that BRM-containing SWI/SNF complexes regulate expression of this gene under physiological conditions. Our studies further de®ne the mechanism by which chromatin-remodeling complexes participate in RB-mediated cell cycle arrest and provide additional novel evidence that the functions of SWI/SNF complexes containing BRG1 or BRM are not completely interchangeable.

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

“…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.…”

“…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).…”

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

“…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.…”

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

“…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).…”

“…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.…”