Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1—which becomes essential in the absence of SMARCB1—but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to the involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as a critical downstream effector of rhabdoid tumor cell transcriptional programs.

Background/Objectives: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. Methods: In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. Results: We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. Conclusions: Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.