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

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dc.contributor.authorMuthuswami, Rohini
dc.contributor.authorBailey, LeeAnn
dc.contributor.authorRakesh, Radhakrishnan
dc.contributor.authorImbalzano, Anthony N.
dc.contributor.authorNickerson, Jeffrey A.
dc.contributor.authorHockensmith, Joel W.
dc.contributor.departmentPediatrics
dc.contributor.departmentBiochemistry and Molecular Pharmacology
dc.date2022-08-11T08:08:24.000
dc.date.accessioned2022-08-23T15:53:42Z
dc.date.available2022-08-23T15:53:42Z
dc.date.issued2019-01-22
dc.date.submitted2019-10-09
dc.description.abstractBrahma-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.
dc.identifier.citation<p>J Cell Physiol. 2019 Jan 22. doi: 10.1002/jcp.28161. [Epub ahead of print] <a href="https://doi.org/10.1002/jcp.28161">Link to article on publisher's site</a></p>
dc.identifier.contextkey15521701
dc.identifier.doi10.1002/jcp.28161
dc.identifier.issn0021-9541 (Linking)
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1636
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2646&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.pmid30667054
dc.identifier.submissionpathfaculty_pubs/1636
dc.identifier.urihttps://hdl.handle.net/20.500.14038/29407
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30667054&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights© 2019 The Authors. Journal of Cellular Physiology. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.source.journaltitleJournal of cellular physiology
dc.subjectBRG1
dc.subjectGleason score
dc.subjectSMARCA4
dc.subjectSWI/SNF
dc.subjectchromatin remodeling
dc.subjectprostate cancer
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectAnalytical, Diagnostic and Therapeutic Techniques and Equipment
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectCancer Biology
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectEnzymes and Coenzymes
dc.subjectGenetic Phenomena
dc.subjectMale Urogenital Diseases
dc.subjectNeoplasms
dc.titleBRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer
dc.typeJournal Article
dspace.entity.typePublication
html.description.abstract<p>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.</p>
refterms.dateFOA2022-08-23T15:53:43Z
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