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Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy

Oncogene volume 30, pages 3289–3294 (2011)Cite this article

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Abstract

Tumor suppressor genes and oncogenes are both commonly altered during carcinogenesis. For oncogenes and other genes that drive growth, targeting mutated or activated forms (such as the EGFR-Her2/Nneu pathway) has been shown to be an effective anti-cancer approach. Pharmacologically targeting tumor suppressor genes has not been as fruitful, as many tumor suppressor genes are irreversibly silenced through somatic mutation or entirely deleted during carcinogenesis, thereby making it difficult to restore gene function. BRM, a key SWI/SNF complex subunit and a putative tumor suppressor gene, is inactivated in 15–20% of many solid tumor types. Unlike other tumor suppressor genes, the loss of BRM has been shown to be a reversible epigenetic change, rather than an irreversible genetic alteration. Using a high throughput drug screen, we identified a number of compounds that could effectively restore BRM expression and function. Two of these compounds, RH (RH02032) and GK (GK0037), were found to be such reactivating agents. Both compounds led to robust re-expression of BRM, induced downstream expression of BRM-dependent genes and inhibited BRM-dependent growth across a wide range of BRM-deficient cancer cell lines of different origins. We therefore show, for the first time, that pharmacologic reversal of epigenetic changes of the SWI/SNF chromatic remodeling complex subunit, BRM, is a potentially viable and novel therapeutic approach.

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Acknowledgements

GL is funded by the Alan B Brown Chair in Molecular Genomics, CCO Chair in Experimental Therapeutics and Population Studies, and the Posluns Family Foundation; Reisman lab funding for this paper is from NCI: R03CA128038–02 and 1R01CA136683–01A1.

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  1. S Gramling and C Rogers: Both authors contributed equally and are considered first authors.

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Florida, Gainesville, FL, USA

    S Gramling, C Rogers & D Reisman

  2. Departments of Medicine and Medical Biophysics, Ontario Cancer Institute, Princess Margaret Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada

    G Liu

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  1. S Gramling
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  2. C Rogers
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  3. G Liu
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  4. D Reisman
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Correspondence to D Reisman.

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Gramling, S., Rogers, C., Liu, G. et al. Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy. Oncogene 30, 3289–3294 (2011). https://doi.org/10.1038/onc.2011.80

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