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Review
. 2022 Aug 24;11(17):2626.
doi: 10.3390/cells11172626.

Beyond SMARCB1 Loss: Recent Insights into the Pathobiology of Epithelioid Sarcoma

Elisa Del Savio  1 , Roberta Maestro  1
Affiliations
Review

Beyond SMARCB1 Loss: Recent Insights into the Pathobiology of Epithelioid Sarcoma

Elisa Del Savio et al. Cells. .

Abstract

Epithelioid sarcoma (ES) is a very rare and aggressive mesenchymal tumor of unclear origin and uncertain lineage characterized by a prevalent epithelioid morphology. The only recurrent genetic alteration reported in ES as yet is the functional inactivation of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), a key component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes. How SMARCB1 deficiency dictates the clinicopathological characteristics of ES and what other molecular defects concur to its malignant progression is still poorly understood. This review summarizes the recent findings about ES pathobiology, including defects in chromatin remodeling and other signaling pathways and their role as therapeutic vulnerabilities.

Keywords: PRC2 (Polycomb Repressive Complex 2); SMARCB1; SWI/SNF; epithelioid sarcoma; soft tissue sarcoma; tazemetostat.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SWI/SNF chromatin remodeling complexes. SWI/SNF complexes are classified into three subgroups: canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). SMARCB1 participates into cBAF and PBAF complexes whilst is not included into the ncBAF ones.
Figure 2
Figure 2
SMARCB1 intersection with relevant pathways. SMARCB1 negatively controls the expression of several cell cycle-related genes. Moreover, by interacting with MYC or GLI1, it hampers their transactivation activity. Conversely, the binding to p53 potentiates p53 tumor suppressive activity. The loss of the SWI/SNF subunits ARID1A, SMARCC1, SMARCC2, and SMARCA4 (in black) has been claimed to play a pathogenic role in the small fraction of SMARCB1-proficient ES.
Figure 3
Figure 3
Functional antagonism between SWI/SNF and PRC2 complexes. SWI/SNF complexes regulate nucleosome remodeling by promoting sliding or ejection of nucleosomes, thus facilitating gene expression. Instead, PRC2 complexes induce chromatin compaction and transcriptional repression by catalyzing methylation of histone H3 on lysine 27 (H3K27).
See this image and copyright information in PMC

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