Re-expression of SMARCA4/BRG1 in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism

Orlando, Krystal A.; Douglas, Amber K; Abudu, Aierken; Wang, Yemin; Tessier‐Cloutier, Basile; Su, Weiping; Peters, Alec; Sherman, Larry S.; Moore, Regan P.; Nguyen, Vinh; Colborne, Shane; Morin, Gregg B.; Kommoss, Friedrich; Lang, Jessica D.; Hendricks, William P.D.; Raupach, Elizabeth A.; Pirrotte, Patrick; Huntsman, David G.; Trent, Jeffrey M.; Parker, Joel S.; Raab, Jesse R.; Weissman, Bernard E.

doi:10.7554/elife.59073

Cited by 21 publications

(20 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our analysis, genes overexpressed in SCCOHT, compared with ECRT SMARCB1 , included those related to intercellular adhesion and neurogenesis, whereas genes overexpressed in ECRT SMARCB1 included those related to skeletal morphogenesis. Interestingly, the observed overexpression of intercellular junction genes in SCCOHT could be in keeping with a recent study which found that re‐expression of SMARCA4 induced an epithelial‐like gene and protein expression programs in SCCOHT cell lines [49]. In addition, we found several transcription factors and HOX genes to be differentially expressed between SCCOHT and ECRT SMARCB1 .…”

Section: Discussionsupporting

confidence: 91%

SMARCA4‐deficient rhabdoid tumours show intermediate molecular features between SMARCB1‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

Andrianteranagna

Cyrta

Masliah‐Planchon

et al. 2021

The Journal of Pathology

View full text Add to dashboard Cite

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1, ECRTSMARCA4, and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics‐based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1, potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the ‘rhabdoid tumour’ spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

show abstract

Section: Discussionsupporting

confidence: 91%

SMARCA4‐deficient rhabdoid tumours show intermediate molecular features between SMARCB1‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

Andrianteranagna

Cyrta

Masliah‐Planchon

et al. 2021

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…AP-1 is a transcription factor that contains dimers of the Jun and Fos proteins with known pro-oncogenic and anti-oncogenic roles [ 27 ]. As it pertains to normal SWI/SNF and AP-1 interactions, their relationship has been increasingly linked to anti-oncogenic processes [ 7 , 25 , 30 , 31 ] where it is thought that AP-1 and SWI/SNF interact through the BAF60a SWI/SNF subunit [ 26 , 32 ] to allow for enhancer selection and activation of cell fate and differentiation gene expression programs [ 26 ]. However, in our study the sites with reduced chromatin accessibility are not associated with cell fate and differentiation genes but rather pro-oncogenic gene categories such as migration, signal transduction, and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells

et al. 2022

View full text Add to dashboard Cite

Malignant rhabdoid tumor (MRT) is driven by the loss of the SNF5 subunit of the SWI/SNF chromatin remodeling complex and then thought to be maintained by residual SWI/SNF (rSWI/SNF) complexes that remain present in the absence of SNF5. rSWI/SNF subunits colocalize extensively on chromatin with the transcription factor MYC, an oncogene identified as a novel driver of MRT. Currently, the role of rSWI/SNF in modulating MYC activity has neither been delineated nor has a direct link between rSWI/SNF and other oncogenes been uncovered. Here, we expose the connection between rSWI/SNF and oncogenic processes using a well-characterized chemical degrader to deplete the SWI/SNF ATPase, BRG1. Using a combination of gene expression and chromatin accessibility assays we show that rSWI/SNF complexes facilitate MYC target gene expression. We also find that rSWI/SNF maintains open chromatin at sites associated with hallmark cancer genes linked to the AP-1 transcription factor, suggesting that AP-1 may drive oncogenesis in MRT. Interestingly, changes in MYC target gene expression are not overtly connected to the chromatin remodeling function of rSWI/SNF, revealing multiple mechanisms used by rSWI/SNF to control transcription. This work provides an understanding of how residual SWI/SNF complexes may converge on multiple oncogenic processes when normal SWI/SNF function is impaired.

show abstract

“…1c-e), suggesting that SWI/SNF components are preserved at conserved MYC sites. Next, to relate our findings to additional cancer settings, we compared binding of MYC-SWI/SNF to BAF155 detected in BRG1-deficient small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), which like MRT is both rare and aggressive and tumorigenesis has been linked directly to multiple mechanisms resulting from loss of a single SWI/SNF subunit (25,26). Remarkably, almost all MYC-SWI/SNF peaks in MRT overlap with chromatin-bound BAF155 that remains following BRG1 loss in the SCCOHT cell line, BIN67, (Fig.…”

Section: Baf155 Is Present At Myc-swi/snf Bound Sites In Other Tumor Cell Typesmentioning

confidence: 99%

Multiple interactions of the oncoprotein transcription factor MYC with the SWI/SNF chromatin remodeler

et al. 2021

View full text Add to dashboard Cite

The SNF5 subunit of the SWI/SNF chromatin remodeling complex has been shown to act as a tumor suppressor through multiple mechanisms, including impairing the ability of the oncoprotein transcription factor MYC to bind chromatin. Beyond SNF5, however, it is unknown to what extent MYC can access additional SWI/SNF subunits or how these interactions affect the ability of MYC to drive transcription particularly in SNF5-null cancers. Here, we report that MYC interacts with multiple SWI/SNF components independent of SNF5. We show that MYC binds the pan-SWI/SNF subunit BAF155 through the BAF155 SWIRM domain, an interaction that is inhibited by the presence of SNF5. In SNF5-null cells, MYC binds with remaining SWI/SNF components to essential genes, although for a purpose that is distinct from chromatin remodeling. Analysis of MYC-SWI/SNF target genes in SNF5-null cells reveals that they are associated with core biological functions of MYC linked to protein synthesis. These data reveal that MYC can bind SWI/SNF in a SNF5-independent manner and that SNF5 modulates access of MYC to core SWI/SNF complexes. This work provides a framework in which to interrogate the influence of SWI/SNF on MYC function in cancers in which SWI/SNF or MYC are altered.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

show abstract

Re-expression of SMARCA4/BRG1 in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism

Cited by 21 publications

References 79 publications

SMARCA4‐deficient rhabdoid tumours show intermediate molecular features between SMARCB1‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

SMARCA4‐deficient rhabdoid tumours show intermediate molecular features between SMARCB1‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells

Multiple interactions of the oncoprotein transcription factor MYC with the SWI/SNF chromatin remodeler

Contact Info

Product

Resources

About