Epigenetic changes in gene expression play an important role in the development and progression of human non-small cell lung carcinoma (NSCLC). Recent studies have shown that patients with tumors possessing one or more epigenetically silenced genes often show a poorer overall survival. Most reports have focused upon two major mechanisms to account for epigenetic modifications, DNA methylation and alterations in histone modifications. However, altered nucleosome positioning at gene promoters represent another important mechanism by which genes can be epigenetically regulated. Indeed, several studies have now implicated chromatin-remodeling complexes in the genesis of epigenetic silencing in human tumor development. In particular, the SWI/SNF (mating type switch/sucrose nonfermenting) chromatin remodeling complex appears like a strong candidate for contributing to epigenetic alterations in NSCLC. Originally identified in yeast, the SWI/SNF complex alters chromatin structure by remodeling nucleosomes through an ATP-dependent process. Loss or expression of the SWI2 ATPase homologs, BRG1 and BRM, by promoter methylation and/or mutations of either or both genes occurs in ~25% of human NSCLC cell lines and ~10% of primary human NSCLCs. Importantly, several groups including our own have shown a correlation between loss of expression of BRG1/BRM and poor prognosis in NSCLC patients. Our published reports and preliminary results demonstrate that reexpression of BRG1 or BRM in deficient NSCLC cells induces expression of many epigenetically silenced genes. Therefore, we hypothesize that loss of SWI/SNF complex activity represents a novel mechanism for gene silencing during NSCLC development. To test this hypothesis, we propose a synergistic research plan using cell culture and genetically engineered mouse models. Specifically, we will determine which gene promoters are activated by BRG1 and/or BRM after reexpression in deficient NSCLC cell lines, discover gene promoters that undergo silencing after loss of BRG1 expression in NSCLC cell lines and assess the effects of BRG1 and/or BRM loss on tumor development in a genetically engineered mouse model for NSCLC. The successful completion of the proposed studies will provide valuable insights into the mechanisms of epigenetic silencing during NSCLC development and of SWI/SNF chromatin remodeling as well as generate a novel genetically engineered animal model for further basic and translational studies. Furthermore, if DNMT or HDAC inhibitors are not effective in reversing gene silencing in the subset of NSCLCs that lack BRG1 and BRM expression, they may require a novel approach for treatment and prevention of progression. By identifying the unique chromatin changes that occur in these tumors and how they differ from BRG1 and/or BRM-positive tumors, we can initiate rational drug design studies to find the reagents to treat this deadly disease.
Non-small cell lung carcinoma remains one of the leading causes of death among adult men and women with little improvement in survival over the past 30 years. We have found a protein complex involved in gene regulation that is lost in at least 10% of these cancers. Importantly, patients whose cancers lack this complex die very quickly from their disease. The studies proposed in this application will help us understand why the loss of this protein complex leads to this poor prognosis. Importantly, our results will eventually guide us in the development of novel treatments to improve the outcome of these patients.
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| Biegel, Jaclyn A; Busse, Tracy M; Weissman, Bernard E (2014) SWI/SNF chromatin remodeling complexes and cancer. Am J Med Genet C Semin Med Genet 166C:350-66 |
| Orvis, Tess; Hepperla, Austin; Walter, Vonn et al. (2014) BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization. Cancer Res 74:6486-6498 |
| Bartlett, Christopher; Orvis, Tess J; Rosson, Gary S et al. (2011) BRG1 mutations found in human cancer cell lines inactivate Rb-mediated cell-cycle arrest. J Cell Physiol 226:1989-97 |
| DelBove, Jessica; Rosson, Gary; Strobeck, Matthew et al. (2011) Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene. Epigenetics 6:1444-53 |
| Cohen, Stephanie M; Chastain 2nd, Paul D; Rosson, Gary B et al. (2010) BRG1 co-localizes with DNA replication factors and is required for efficient replication fork progression. Nucleic Acids Res 38:6906-19 |
