The MYC–SWI/SNF connection in rhadboid tumors

Rhabdoid tumors (RT) are rare and aggressive childhood cancers with no effective treatment options and high rates of mortality. RT are unusual among malignancies in that their etilolgy is tied to mutations in just one gene, SMARBC1, which encodes the SNF5 component of the SWI/SNF chromatin remodeler. Our interest in RT was piqued by reports that MYC target gene signatures are repeatedly activated in RT patient transcriptomes, despite there being no obvious alterations to MYC itself. 

SNF5 binds directly to MYC. We recently found that SNF5 inhibits the DNA binding capability of MYC, both in vitro and in cells. Reintroduction of SNF5 into RT cell lines decreases binding by MYC genome wide (left panel, below), providing a simple explanation for the recurring activation of MYC target genes in RT patient samples. Supporting this idea, if we compare the primary transcriptional effects of SNF5 reintroduction with MYC inhibition (we used OmoMYC, a protein-based MYC inhibitor), they are very similar (right two panels, below; read the paper if you want to know what this figure shows!).

We hypothesize that, in the absence of SNF5, MYC has unfettered access to its target genes, which it then binds to regulate oncogenic transcriptional processes in SNF5-null cancers. This view predicts that MYC is a defacto driver of malignant processes in RT, and that these cancers will thus be sensitive to MYC inhibitors, when they become available. 

We seek to understand the full role of MYC in sculpting the tumorigenic RT transcriptome, to determine whether MYC inhibition is a viable route to an anti-RT therapy, and to explore other intriguing connections we have uncovered between MYC and the SWI/SNF chromatin remodeling complex. 


© Bill Tansey 2019