The MYC-SWI/SNF connection in cancers defined by SMARCA4 mutations - PROJECT SUMMARY/ABSTRACT Approximately 20% of all cancers harbor deleterious mutations to subunits of the SWI/SNF chromatin remodeling complex. Determining how SWI/SNF subunit loss drives malignancy in cancers defined by SWI/ SNF subunit mutations has remained an active area of research. A newly emerging area of study in these tumor types involves the intersection of SWI/SNF with established oncogenic pathways as a means to control tumor suppression and formation—with one of these oncogenic pathways implicating the oncoprotein transcription factor, MYC. As a transcription factor, MYC binds to and regulates expression of thousands of genes, which is dependent on a suite of cofactor interactions MYC makes with chromatin regulators, coactivators, and corepressors. In our previous studies, we discovered that the SNF5 subunit of SWI/SNF can directly antagonize MYC function at the level of chromatin and in SNF5-null rhabdoid cancer cell lines, MYC can interact with additional SWI/SNF subunits to promote MYC target gene expression. In this application, we posit that additional SWI/SNF subunits beyond SNF5—specifically the BRG1 subunit of SWI/SNF—also function in tumor suppression through directly impeding MYC functionality. This implies that loss of BRG1 in cancer, leads to changes in MYC and/or SWI/SNF activities that promote the cancer state. Support for this hypothesis comes from evidence that activation of MYC target genes is present in BRG1- null tumors and reintroduction of BRG1 suppresses cancer processes and growth, which is proposed to be due to SWI/SNF interactions with transcription factors such as MYC and AP-1. Published data also indicate that re-expression of BRG1 antagonizes MYC activity on chromatin, suggesting that BRG1—like SNF5— can control MYC function. Overall, these data provide the rationale for examining the MYC-SWI/SNF connection in BRG1-null cancers and point to the possibility there there are broad oncogenic mechanisms at work across cancers defined by SWI/SNF subunit mutations. Specific Aim 1 will use a battery of genetic and genomic approaches to determine how MYC and SWI/SNF regulate genomic activities in diverse BRG1-null cancer cells. Specific Aim 2 will directly challenge the hypothesis that BRG1 can temper MYC function across the genome. Completion of these studies will expose the oncogenic mechanisms that maintain the BRG1-null cancer state and challenge the significance of SWI/SNF in controlling MYC target gene expression.
