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

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

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 t...

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Bibliographic Details
Published in:Oncogenesis (New York, NY) Vol. 11; no. 1; pp. 30 - 12
Main Authors: Moe, Kylie C., Maxwell, Jack N., Wang, Jing, Jones, Cheyenne A., Csaki, Grace T., Florian, Andrea C., Romer, Alexander S., Bryant, Daniel L., Farone, Anthony L., Liu, Qi, Tansey, William P., Weissmiller, April M.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01-06-2022
Nature Publishing Group
Subjects:
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631/67/395
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Activator protein 1
Apoptosis
BRG1 protein
Cell Biology
Chromatin remodeling
Gene expression
Human Genetics
Internal Medicine
Malignant rhabdoid tumor
Medicine
Medicine & Public Health
Myc protein
Oncology
Transcription factors
Tumorigenesis
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Summary: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.
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ISSN:2157-9024
2157-9024
DOI:10.1038/s41389-022-00406-6