Abstract
Abstract BRG1, encoding an ATPase of the SWI/SNF chromatin remodelling complex, is genetically inactivated in a variety of human solid tumors, especially non-small cell lung cancer, thus, constituting a bona fide tumor suppressor gene. However, the mechanisms that mediate the tumor suppressor function of BRG1 are not completely elucidated. We previously reported that lung tumors with amplification at any of the MYC family of genes lacked BRG1 mutations, suggesting a functional relationship between both proteins. Using isogenic lung cancer cell lines, that stably and conditionally express wild type or mutant BRG1, we found that wtBRG1 induced the up-regulation of MYC-target genes. This was accompanied by a reduction in MYC levels. Interestingly, we observed an overlap in the gene expression pattern after restoring wtBRG1 in lung cancer cells and gene expression in normal lung, indicating that BRG1 is promoting cell differentiation. In addition, the effects of BRG1 activity in lung cancer cells, i.e. changes in morphology and in gene expression depended on the presence of specific vitamins/hormones. Exposition to these compounds conferred lung cancer cells specific morphological features that were compatible with cell differentiation, only after restoring wtBRG1. Finally, using lung orthotopic mouse models we demonstrated that BRG1 was able to cause significant tumor shrinkage and delay tumor progression. Taken together our data support a tight functional relationship between BRG1 and MYC by which inactivation of BRG1 in cancer cells leads to de-regulation of MYC activity and allow refractoriness to nuclear receptor-mediated external signals impairing the control important cellular processes, such as cell differentiation, proliferation and response to inflammation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4022. doi:10.1158/1538-7445.AM2011-4022
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