Frequent Loss of Brm Expression in Gastric Cancer Correlates with Histologic Features and Differentiation State

Abstract

The mammalian SWI/SNF chromatin remodeling complex, an essential epigenetic regulator, contains either a single Brm or BRG1 molecule as its catalytic subunit. We observed frequent loss of Brm expression but not of BRG1 in human gastric cancer cell lines. Treatment with histone deacetylase inhibitor rescued Brm expression, indicating epigenetic regulation of this gene, and an RNA interference-based colony formation assay revealed antioncogenic properties of Brm. Brm immunostaining of 89 primary gastric cancers showed an obvious reduction in 60 cases (67%) and a severe decrease in 37 cases (42%). Loss of Brm is frequent in the major gastric cancer types (well-or moderately-differentiated tubular adenocarcinoma and poorly-differentiated adenocarcinoma) and positively correlates with the undifferentiated state. Among the minor gastric cancer types, Brm expression persists in signetring cell carcinoma and mucinous adenocarcinoma, but a marked decrease is observed in papillary adenocarcinoma. Intestinal metaplasia never shows decreased expression, indicating that Brm is a valid marker of gastric oncogenesis. In contrast, BRG1 is retained in most cases; a concomitant loss of BRG1 and Brm is rare in gastric cancer, contrary to other malignancies. We further show that Brm is required for villin expression, a definitive marker of intestinal metaplasia and differentiation. Via regulating such genes important for gut differentiation, Brm should play significant roles in determining the histologic features of gastric malignancy. [Cancer Res 2007;67(22):10727-35]

MicroRNAs miR-199a-5p and -3p Target the Brm Subunit of SWI/SNF to Generate a Double-Negative Feedback Loop in a Variety of Human Cancers

“…When we exogenously expressed Brm in such deficient cell lines, this resulted in a reduced oncogenic potential, suggesting that Brm has tumor-suppressive properties. This possibility is consistent with our observations that a frequent loss of Brm expression in gastric cancers correlates with a less differentiated state (14). However, the molecular mechanisms underlying the posttranscriptional suppression of Brm remained to be elucidated.…”

“…In terms of the Brm catalytic subunit, we and others have reported that it is frequently deficient in various cancer cell lines such as SW13, AZ521, and C33A (15) and also in primary tumors of the lung (16), stomach (14), and prostate (17). We have, however, further found that a functional Brm gene is present and actively transcribed in all of the Brm-deficient cell lines that we tested in nuclear run-on transcription assays (15,18).…”

“…These transcriptional regulators recruit the complex to different gene promoters, leading to transcriptional activation or repression (12). In addition, it is now known that the Brm-type and BRG1 type SWI/SNF complexes regulate a set of promoters that do not fully overlap (7,9,13,14).…”

ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1

“…However, it is possible that BRG1 could have different, or even opposing, roles depending on the tissue, the factors (oncogenic or anti-oncogenic) with which BRG1 interacts and/or the functional activity of various proteins within the SWI/SNF complex. For instance, while BRM expression is frequently lost in tumors affecting the alimentary tract (in particular gastric carcinomas), BRG1 is usually retained (Yamamichi et al, 2007). In fact, BRG1 may act in an oncogenic manner in some tumors (Wang et al, 2009).…”

Roles of SWI/SNF Complex Genes in Breast Cancer

“…At least haploinsufficiency of BRG1 is recognized [25][26][27]62], while further studies are necessary whether such a role exists for STK11/LKB1 or not. Similar to BRG1, abnormalities of BRM in various cancers have been reported [58][59][60][61][63][64][65][66][67][68][69]. Though the early studies of cell lines and animal models strongly suggested subunits of SWI/SNF proteins as tumor suppressor, the first definitive evidence that members of these complexes function as tumor suppressive was shown by Versteege and colleagues.…”