Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma

Jin, J. X.; Fuchslocher, F.; Carreno-Gonzalez, M. J.; Zahnow, F.; Ceranski, A. K.; Will, R.; Helm, D.; Bestvater, F.; Banito, A.; Imle, R.; Ohmura, S.; Cidre-Aranaz, F.; Gruenewald, T. G. P.

doi:10.1101/2024.09.18.613695

bioRxiv · 10.1101/2024.09.18.613695

Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma

Jin, J. X.·Fuchslocher, F.·Carreno-Gonzalez, M. J.·Zahnow, F.·Ceranski, A. K.·Will, R.·Helm, D.·Bestvater, F.·Banito, A.·Imle, R.·Ohmura, S.·Cidre-Aranaz, F.·Gruenewald, T. G. P.

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Abstract

Dysfunction of epigenetic modulators, such as the SWI/SNF complex, is a wide-spread but relatively ill-defined feature of a broad spectrum of cancer entities. Among SWI/SNF-mutant entities, SMARCB1-deficient cancers, such as the highly aggressive Epithelioid Sarcoma (EpS), are characterized by this genetic event in an otherwise rather silent mutational landscape. This renders EpS an ideal model to study how epigenetic reprogramming by a single mutation can contribute to tumorigenesis. Hence, to characterize and compare the function of the SMARCB1-deficient, residual and the physiological SWI/SNF complex in cancer, we generated a panel of SMARCB1 re-expressing EpS cell lines and employed a functional multi-omics approach. Here, 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. We further demonstrate that EpS cell lines depend on residual SWI/SNF action to maintain clonogenicity and proliferation. Consequently, EpS cell lines exhibit markedly increased sensitivity to pharmacological inhibition of the residual SWI/SNF when compared with SWI/SNF-proficient cancer entities. Collectively, our results from the EpS model shed new light on how a single mutation can rewire the pleiotropic effects of an epigenetic master regulator and provide inroads for therapeutic intervention.

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Jin, J. X., Fuchslocher, F., Carreno-Gonzalez, M. J., Zahnow, F., Ceranski, A. K., Will, R., Helm, D., Bestvater, F., Banito, A., Imle, R., Ohmura, S., Cidre-Aranaz, F., Gruenewald, T. G. P.. 2024-09-22. Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma. https://doi.org/10.1101/2024.09.18.613695

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