University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Department of Pediatrics; Imbalzano Lab; Nickerson Lab

Publication Date

2019-01-22

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Analytical, Diagnostic and Therapeutic Techniques and Equipment | Biochemistry, Biophysics, and Structural Biology | Cancer Biology | Cell Biology | Cells | Cellular and Molecular Physiology | Enzymes and Coenzymes | Genetic Phenomena | Male Urogenital Diseases | Neoplasms

Abstract

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.

Keywords

BRG1, Gleason score, SMARCA4, SWI/SNF, chromatin remodeling, prostate cancer

Rights and Permissions

© 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.

DOI of Published Version

10.1002/jcp.28161

Source

J Cell Physiol. 2019 Jan 22. doi: 10.1002/jcp.28161. [Epub ahead of print] Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Journal of cellular physiology

PubMed ID

30667054

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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