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The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

Oncogene volume 26, pages 7058–7066 (2007)Cite this article

Abstract

The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRM-related gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.

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Acknowledgements

We thank Rachel Dresbeck for her diligent efforts in editing this manuscript. This work is supported in part by University of Michigan Diabetes Core grant DK20572, University of Michigan Cancer Center grant 5-P30-CA46592 and K08 grant CA092149–03. Christian Murchardt has received grant support from ‘Canceropole IdF’. Thanks to Drs Aubrey Thompson and Thomas Carey for their critical feedback on this manuscript. We also thank Drs Kleer, Tom Giordano, David Beer, Rajal Shah and Kathy Cho for their gift of the breast, colon, esophageal, bladder and ovarian TMAs respectively.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA

    S Glaros, G M Cirrincione & D Reisman

  2. Département de Biologie du Développement, Expression Génétique et Maladies, URA1644 du CNRS, Institut Pasteur, Bât. Fernbach, Rue du Docteur Roux, Paris Cedex, France

    C Muchardt

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    C G Kleer & C W Michael

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  1. S Glaros
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  2. G M Cirrincione
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  5. C W Michael
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  6. D Reisman
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Correspondence to D Reisman.

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Supplementary information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Glaros, S., Cirrincione, G., Muchardt, C. et al. The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26, 7058–7066 (2007). https://doi.org/10.1038/sj.onc.1210514

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