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/BAF47 gene, a component of the SWI/SNF chromatin remodeling complex, occur in virtually all malignant rhabdoid tumors (MRTs). The SWI/SNF complex acts as a global transcriptional activator that alters nucleosome positioning on DNA via an energy-dependent mechanism. During the previous funding period, we have determined that loss of SNF5 expression affects cell cycle regulation in all MRT cell lines. We also developed 2 genetically engineered mouse (GEM) models for MRT development where loss of expression of the pRb family members or decreased expression of p53 accelerates the appearance of spinal cord MRTs. Importantly, our preliminary studies have now put forward 4 candidate genes suspected of supporting SNF5 tumor suppressor action. Based on these results, we hypothesize that loss of SNF5 expression can lead to MRT development through disruption of neural differentiation. To test this hypothesis, we propose 3 specific aims. In the first specific aim, we will characterize novel targets of SNF5 in human MRT cell lines using Taq-Man(R) assays, Western blotting and ChIPs, determine their role in MRT oncogenesis using cell culture models and assess the effects of SNF5 loss on chromatin structure and modifications in their promoter regions. The second specific aim will identify downstream targets of SNF5 associated with MRT development using a combination of high-throughput DNA sequencing approach (ChIP-seq) and gene expression array analyses. In the third specific aim, we will determine the role of Snf5 inactivation in neural cell development and malignant rhabdoid tumorigenesis using novel genetically engineered mouse models, neurosphere cultures and a comparison of mouse spinal cord MRTs with human MRTs of the central nervous system. The dissection of the role SNF5 plays in MRT development will broaden our understanding of its normal biological and biochemical activities, provide new insights into the function of the SWI/SNF complex in cell cycle regulation and normal development and identify new avenues of treatment for this highly aggressive tumor.
Tumor suppressor genes are turned off in many human cancers and are often responsible for the familial forms of this disease. We are studying one of these genes called INI1/SNF5/BAF47 that plays an important role in the development of an aggressive childhood cancer of the kidney, brain and soft tissues called malignant rhabdoid tumor (MRT). Our previous studies have suggested that the loss of this gene before or early after birth may interfere with normal nervous system development leading to the appearance of MRT in children. This current grant will carry out further studies to test this hypothesis using MRT cells grown in culture, DNA and protein from these cells and genetically-modified mice that will lose INI1/SNF5/BAF47 expression in nervous tissues. By doing these studies, we will broaden our understanding of its normal biological and biochemical activities and identify new avenues of treatment for this highly aggressive tumor.
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