The BRG1 ATPase of Human SWI/SNF Chromatin Remodeling Enzymes as a Driver of Cancer

Wu, Qiong; Lian, Jane B.; Stein, Janet L.; Nickerson, Jeffrey A.; Imbalzano, Anthony N.

doi:10.2217/epi-2017-0034

Cited by 102 publications

(95 citation statements)

References 123 publications

(148 reference statements)

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“…3.1 | BRG1 expression is elevated in prostate tumors relative to normal tissue BRG1 and BRM, two closely related ATPases that are mutually exclusive catalytic subunits of mammalian SWI/SNF chromatin remodeling enzymes, have different functional roles in different types of cancer (Hodges et al, 2016;Savas & Skardasi, 2018;Wu et al, 2017). Prior reports about BRG1/BRM in prostate cancer have utilized immunohistochemistry (IHC) of patient tumor samples and determined that BRG1 protein levels were higher in tumor than in normal tissue.…”

Section: Resultsmentioning

confidence: 99%

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BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

Muthuswami

Bailey

Radhakrishnan

et al. 2019

Journal Cellular Physiology

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Brahma‐related gene 1 (BRG1) is one of two mutually exclusive ATPases that function as the catalytic subunit of human SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling enzymes. BRG1 has been identified as a tumor suppressor in some cancer types but has been shown to be expressed at elevated levels, relative to normal tissue, in other cancers. Using TCGA (The Cancer Genome Atlas) prostate cancer database, we determined that BRG1 mRNA and protein expression is elevated in prostate tumors relative to normal prostate tissue. Only 3 of 491 (0.6%) sequenced tumors showed amplification of the locus or mutation in the protein coding sequence, arguing against the idea that elevated expression due to amplification or expression of a mutant BRG1 protein is associated with prostate cancer. Kaplan‐Meier survival curves showed that BRG1 expression in prostate tumors inversely correlated with survival. However, BRG1 expression did not correlate with Gleason score/International Society of Urological Pathology (ISUP) Grade Group, indicating it is an independent predictor of tumor progression/patient outcome. To experimentally assess BRG1 as a possible therapeutic target, we treated prostate cancer cells with a biologic inhibitor called ADAADi (active DNA‐dependent ATPase A Domain inhibitor) that targets the activity of the SNF2 family of ATPases in biochemical assays but showed specificity for BRG1 in prior tissue culture experiments. The inhibitor decreased prostate cancer cell proliferation and induced apoptosis. When directly injected into xenografts established by injection of prostate cancer cells in mouse flanks, the inhibitor decreased tumor growth and increased survival. These results indicate the efficacy of pursuing BRG1 as both an indicator of patient outcome and as a therapeutic target.

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Section: Resultsmentioning

confidence: 99%

“…Elevated BRG1 expression has been linked to numerous pathways converging on cell proliferation and survival, including sonic hedgehog (SHH) and WNT signaling, the PI3K/AKT pathway, and regulation of lipogenesis and ATP-binding cassette (ABC) transporter induction (reviewed in [Wu et al, 2017]).…”

mentioning

confidence: 99%

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

Muthuswami

Bailey

Radhakrishnan

et al. 2019

Journal Cellular Physiology

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“…These enzymes are widely utilized in the cell to regulate gene expression, replication, repair, recombination, and higher-order genome organization. Not surprisingly, both enzymes have been implicated in diverse types of cancer (14)(15)(16). There is considerable evidence that both the BRG1 and the BRM enzymes are mutated or exhibit altered expression in many cancers, but to date, the evidence suggests that the consequences of these changes vary widely depending on the type of cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Elevated BRG1 expression has been linked to numerous pathways converging on cell proliferation and survival, including SHH and WNT signaling, the PI3K/AKT pathway, and regulation of lipogenesis and ABC transporter induction (reviewed in (16)).…”

Section: Introductionmentioning

confidence: 99%

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

Muthuswami

Bailey

Radhakrishnan

et al. 2018

Preprint

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BRG1 is one of two mutually exclusive ATPases that function as the catalytic subunit of human SWI/SNF chromatin remodeling enzymes. BRG1 has been identified as a tumor suppressor in some cancer types but has been shown to be expressed at elevated levels, relative to normal tissue, in other cancers. Using the TCGA (The Cancer Genome Atlas) prostate cancer database, we determined that BRG1 mRNA and protein expression is elevated in prostate tumors relative to normal prostate tissue. Only 3 of 491 (0.6%) sequenced tumors showed amplification of the locus or mutation in the protein coding sequence, arguing against the idea that elevated expression due to amplification or expression of a mutant BRG1 protein is associated with prostate cancer. Kaplan-Meier survival curves showed that BRG1 expression in prostate tumors inversely correlated with survival. However, BRG1 expression did not correlate with Gleason score/ISUP Grade Group, indicating it is an independent predictor of tumor progression/patient outcome. To experimentally assess BRG1 as a possible therapeutic target, we treated prostate cancer cells with a biologic inhibitor called ADAADi that targets the activity of the SNF2 family of ATPases in biochemical assays but showed specificity for BRG1 in prior tissue culture experiments. The inhibitor decreased prostate cancer cell proliferation and induced apoptosis.When directly injected into xenografts established by injection of prostate cancer cells in mouse flanks, the inhibitor decreased tumor growth and increased survival. These results indicate the efficacy of pursuing BRG1 as both an indicator of patient outcome and as a therapeutic target.

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“…We have also started to understand that at different stages of certain tumors SWI/SNF complexes can act either as tumor suppressors or as oncogenes . These mechanistic insights are providing new therapeutic opportunities, and targeting SWI/SNF subunits has great potential for the development of novel cancer therapies, and several efforts are ongoing to develop BRG1 inhibitors …”

Section: Introductionmentioning

confidence: 99%

Structure of the BRK domain of the SWI/SNF chromatin remodeling complex subunit BRG1 reveals a potential role in protein–protein interactions

2020

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BRG1/SMARCA4 and its paralog BRM/SMARCA2 are the ATPase subunits of human SWI/SNF chromatin remodeling complexes. These multisubunit assemblies can act as either tumor suppressors or drivers of cancer, and inhibiting both BRG1 and BRM, is emerging as an effective therapeutic strategy in diverse cancers. BRG1 and BRM contain a BRK domain. The function of this domain is unknown, but it is often found in proteins involved in transcription and developmental signaling in higher eukaryotes, in particular in proteins that remodel chromatin. We report the NMR structure of the BRG1 BRK domain. It shows similarity to the glycine‐tyrosine‐phenylalanine (GYF) domain, an established protein–protein interaction module. Computational peptide‐binding‐site analysis of the BRK domain identifies a binding site that coincides with a highly conserved groove on the surface of the protein. This sets the scene for experiments to elucidate the role of this domain, and evaluate the potential of targeting it for cancer therapy.

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The BRG1 ATPase of Human SWI/SNF Chromatin Remodeling Enzymes as a Driver of Cancer

Cited by 102 publications

References 123 publications

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

Structure of the BRK domain of the SWI/SNF chromatin remodeling complex subunit BRG1 reveals a potential role in protein–protein interactions

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