The BRG-1 Subunit of the SWI/SNF Complex Regulates CD44 Expression

Abstract

Aberrant regulation of CD44, a transmembrane glycoprotein, has been implicated in the growth and metastasis of numerous tumors. Although both CD44 overexpression and loss have been implicated in tumor progression, the mechanism of CD44 down-regulation in these tumor types is not known. By immunoblot and reverse transcription-polymerase chain reaction analysis we determined that a cervical carcinoma cell line, C33A, lacks CD44 expression. To determine how CD44 is down-regulated in C33A cells, we utilized cell fusions of C33A cells with a CD44-expressing cell line (SAOS-2). We found that SAOS-2 fusion restored CD44 expression in C33A cells, suggesting that a trans-acting factor present in SAOS-2 cells promotes CD44 production. C33A cells are BRG-1-deficient, and we found that CD44 was absent in another BRG-1-deficient tumor cell line, indicating that loss of BRG-1 may be a general mechanism by which cells lose CD44. Reintroduction of BRG-1 into these cells restored CD44 expression. Furthermore, disruption of BRG-1 function through the use of dominant-negative BRG-1 demonstrated the requirement of BRG-1 in CD44 regulation. Finally, we show that Cyclin E overexpression resulted in the attenuation of CD44 stimulation, which is consistent with previous observations that Cyclin E can abrogate BRG-1 action. Taken together, these results suggest that BRG-1 is a critical regulator of CD44 expression, thus implicating SWI/SNF components in the regulation of cellular adhesion and metastasis.The CD44 family of transmembrane glycoproteins has been implicated in cell-cell and cell-matrix adhesion, cell growth, and metastasis (1-3). A number of different CD44 proteins are produced through alternative RNA splicing, and these proteins are extensively modified. Many tumors express higher than normal levels of total CD44 protein as well as splice variants that do not occur in normal cells (1,3, 4). How CD44 expression is regulated in normal cells and in tumors is poorly understood.A role for CD44 in tumor progression has been documented in numerous clinical and experimental studies (1, 2). Ectopic expression of some forms of CD44 can enhance metastasis and tumor growth both in vitro and in vivo (5-7). It is believed that CD44 expression in some tumors increases as the tumor becomes more proliferative and invasive (1). These findings suggest that CD44 might be regulated by environmental or genetic factors that have been shown to contribute to cancer progression. The expression of activated oncogenes like v-Ras, v-Src, and v-Fos, which promote transformation and invasion, have been reported to induce CD44 expression (8 -10). In addition, the epidermal growth factor receptor has also been shown to stimulate CD44 (10,11).In contrast to studies that correlate CD44 overexpression with cancer progression, a significant number of reports also indicate that loss of CD44 expression can contribute to tumorigenesis (12). Specifically, it has been shown that loss of CD44 in cervical carcinomas, neuroblastomas, prostate carcinomas, melanomas, an...

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“…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).…”