MYC regulates a DNA repair gene expression program in small cell carcinoma of the ovary, hypercalcemic type
SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of all 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, is 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 like it, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF, BRG1, and MYC that has yet to be fully explored.  In this study we investigate the contribution of MYC to SCCOHT biology through chromatin binding and transcriptome analysis performed in genetically engineered cell lines and patient tumor data. We find that MYC binds to thousands of active promoters in the BIN-67 cell line, and that depletion of MYC results in a broad range of gene expression changes with a notable effect on expression of genes related to DNA repair. We identify a MYC-regulated DNA repair gene expression program in BIN-67 cells that is oppositely regulated by BRG1 in an ATPase-independent manner. Finally, we uncover a DNA repair gene signature that is glaringly upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit, SNF5. 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. Overall design: We used the SCCOHT cell line, BIN-67, to interrogate the contribution of MYC to the SCCOHT transcriptome. We engineered BIN-67 cells to express a version of MYC that can be depleted in cells using a dTAG chemical degrader called dTAGV-1. We performed chromatin binding assays (CUT&RUN) in untreated engineered cells. We performed RNA-seq on engineered cells treated with dTAGV-1, to deplete MYC, alongside  a vehicle control or negative chemical control (dTAGV-1-NEG). Cells were collected 24 hr post-treatment.  We then validated our transcriptome findings using patient tumor data.