Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ChIP-Seq]

Dysfunction of epigenetic modulators such as the SWI/SNF complex is involved in a wide spectrum of cancer entities, yet their precise role in carcinogenesis is not clear to date Among SWI/SNF-mutant entities, SMARCB1-deficient cancers such as Epithelioid Sarcoma (EpS) are characterized by this genetic event in an otherwise rather silent mutational landscape. However, its oncogenic role remains unclear. Here, we generate a panel of SMARCB1 re-expressing Epithelioid Sarcoma (EpS) cell lines and employ a functional multi-omics approach to characterize and compare the function of the residual SMARCB1-deficient and the physiological SWI/SNF complex in EpS. We show that SWI/SNF holds canonical characteristics of both tumor-suppressors and proto-oncogenes due to its multi-faceted role in the regulation of the epigenome. Our data indicates that the loss of SMARCB1 causes an overall loss of SWI/SNF chromatin affinity at cis-regulatory enhancer elements, inducing a preference for uncontrolled proliferation and cell cycle progression as opposed to development and differentiation. As epigenetic regulation is a dynamic complex, we further demonstrate that EpS cell lines depend on continuous residual SWI/SNF action to maintain clonogenicity and proliferation. Consequently, our models exhibit markedly increased sensitivity to pharmacological inhibition of the residual SWI/SNF when compared with SWI/SNF-proficient cancer entities. Collectively, our results shed new light on the pleiotropic, deregulated pathways upon SWI/SNF dysfunction in EpS and provide inroads for further therapeutic approaches. Overall design: ChIP-Seq for H3K4me3, H3K27me3, H3K27ac, BRG1, SMARCB1 (aliases: BAF47/hSNF5/INI-1) in stable isogenic VA-ES-BJ EpS cell lines in 2 biological replicates with/without (tetON) re-expression of SMARCB1.