SWI/SNF Chromatin Remodeling Loss and Human Cancer

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DESCRIPTION (provided by applicant): The identification of tumor suppressor genes has led to new insights into the mechanisms of human cancer development. The normal functions of these genes often lie in the control of gene expression, especially in the realm of cell cycle control and cellular differentiation. Several recent studies have implicated aberrant activity of chromatin remodeling complexes in the development of human cancer. Mutations in the INI1/SNF5 gene, a component of the SWI/SNF chromatin remodeling complex, occur in the majority of malignant rhabdoid tumors. The SWI/SNF complex acts as a global transcriptional activator that alters nucleosome positioning on DNA via an energy-dependent mechanism. Others and we have also demonstrated the loss and/or mutations of both human SWI2 homologs, BRG1 and BRM, in human tumor cell lines and primary tumors. Loss of expression of both proteins abrogates Rb-mediated cell cycle arrest. However either protein appears to regulate the expression of key cancer progression genes including Ecadherin and CD44. Furthermore, while BRG1v/- mice develop adenocarcinomas, BRM-/- mice do not show an increased tumor incidence. Therefore, the mechanism by which loss of expression of either or both proteins contributes to the etiology of human cancers remains unresolved. We have observed an association between BRG1-induced gene expression and loss of promoter methylation in human tumor cells, especially Non-Small Cell Lung Carcinomas (NSCLC). Based on these studies, we hypothesize that loss of SWI/SNF complex activity through inactivation of BRG1 and/or BRM fuels genomic instability during human tumor progression by facilitating gene silencing through DNA methylation. To test this hypothesis, we require a better understanding how loss of expression of BRG1 and BRM proteins alters the biological properties of tumor cells and the chromatin structure of cancer related genes. In this application, we will identify overlapping and independent biological and biochemical functions of these proteins in the first specific aim. In the second specific aim, we will determine how the loss of these proteins contributes to lung tumor development using a human tracheobronchial cell culture model. In the last specific aim, we will characterize the effects of BRG1 and BRM loss on the chromatin structure and DNA methylation status of important target genes. The dissection of the role of these genes in human cancer development will broaden our understanding of their normal biological and biochemical functions, provide new insights into the control of DNA methylation and impact upon treatment and detection of this clinically important tumor.