Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

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

Subjects

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Betz BL, Strobeck MW, Reisman DN, Knudsen ES, Weissman BE . (2002). Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RB. Oncogene 21: 5193–5203.

    Article  CAS  PubMed  Google Scholar 

  • Bourachot B, Yaniv M, Muchardt C . (2003). Growth inhibition by the mammalian SWI-SNF subunit Brm is regulated by acetylation. EMBO J 22: 6505–6515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlson M, Laurent BC . (1994). The SNF/SWI family of global transcriptional activators. Curr Opin Cell Biol 6: 396–402.

    Article  CAS  PubMed  Google Scholar 

  • DeCristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W, Weissman BE . (2001). Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies. J Cell Physiol 186: 136–145.

    Article  CAS  PubMed  Google Scholar 

  • Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J et al. (1994). The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79: 119–130.

    Article  CAS  PubMed  Google Scholar 

  • Glaros S, Cirrincione GM, Muchardt C, Kleer CG, Michael CW, Reisman D . (2007). The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26: 7058–7066.

    Article  CAS  PubMed  Google Scholar 

  • Gramling S, Reisman D . (2011). Discovery of BRM targeted therapies: novel reactivation of an anticancer gene. Lett Drug Des Discov 8: 93–99.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hendricks KB, Shanahan F, Lees E . (2004). Role for BRG1 in cell cycle control and tumor suppression. Mol Cell Biol 24: 362–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klochendler-Yeivin A, Muchardt C, Yaniv M . (2002). SWI/SNF chromatin remodeling and cancer. Curr Opin Genet Dev 12: 73–79.

    Article  CAS  PubMed  Google Scholar 

  • Liu R, Liu H, Chen X, Kirby M, Brown PO, Zhao K . (2001). Regulation of CSF1 promoter by the SWI/SNF-like BAF complex. Cell 106: 309–318.

    Article  CAS  PubMed  Google Scholar 

  • Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J et al. (2008). Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mutat 29: 617–622.

    Article  CAS  PubMed  Google Scholar 

  • Mizutani T, Ito T, Nishina M, Yamamichi N, Watanabe A, Iba H . (2002). Maintenance of integrated proviral gene expression requires Brm, a catalytic subunit of SWI/SNF complex. J Biol Chem 277: 15859–15864.

    Article  CAS  PubMed  Google Scholar 

  • Morrison AJ, Shen X . (2006). Chromatin modifications in DNA repair. Results Probl Cell Differ 41: 109–125.

    Article  CAS  PubMed  Google Scholar 

  • Muchardt C, Bourachot B, Reyes JC, Yaniv M . (1998). ras transformation is associated with decreased expression of the brm/SNF2alpha ATPase from the mammalian SWI-SNF complex. EMBO J 17: 223–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peterson CL, Workman JL . (2000). Promoter targeting and chromatin remodeling by the SWI/SNF complex. Curr Opin Genet Dev 10: 187–192.

    Article  CAS  PubMed  Google Scholar 

  • Reisman D, Glaros S, Thompson EA . (2009). The SWI/SNF complex and cancer. Oncogene 28: 1653–1668.

    Article  CAS  PubMed  Google Scholar 

  • Reisman DN, Strobeck MW, Betz BL, Sciariotta J, Funkhouser Jr W, Murchardt C et al. (2002). Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression. Oncogene 21: 1196–1207.

    Article  CAS  PubMed  Google Scholar 

  • Reisman DN, Sciarrotta J, Bouldin TW, Weissman BE, Funkhouser WK . (2005). The expression of the SWI/SNF ATPase subunits BRG1 and BRM in normal human tissues. Appl Immunohistochem Mol Morphol 13: 66–74.

    Article  CAS  PubMed  Google Scholar 

  • Reisman DN, Sciarrotta J, Wang W, Funkhouser WK, Weissman BE . (2003). Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res 63: 560–566.

    CAS  PubMed  Google Scholar 

  • Roberts CW, Leroux MM, Fleming MD, Orkin SH . (2002). Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2: 415–425.

    Article  CAS  PubMed  Google Scholar 

  • Sansam CG, Roberts CW . (2006). Epigenetics and cancer: altered chromatin remodeling via Snf5 loss leads to aberrant cell cycle regulation. Cell Cycle 5: 621–624.

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Powers N, Saini N, Comstock CE, Sharma A, Weaver K et al. (2008). The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer. Cancer Res 68: 10154–10162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simone C . (2006). SWI/SNF: the crossroads where extracellular signaling pathways meet chromatin. J Cell Physiol 207: 309–314.

    Article  CAS  PubMed  Google Scholar 

  • Strobeck MW, Reisman DN, Gunawardena RW, Betz BL, Angus SP, Knudsen KE et al. (2002). Compensation of BRG-1 function by Brm: insight into the role of the core SWI-SNF subunits in retinoblastoma tumor suppressor signaling. J Biol Chem 277: 4782–4789.

    Article  CAS  PubMed  Google Scholar 

  • Strober BE, Dunaief JL, Guha, Goff SP . (1996). Functional interactions between the hBRM/hBRG1 transcriptional activators and the pRB family of proteins1. Mol Cell Biol 16: 1576–1583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Cote J, Xue Y, Zhou S, Khavari PA, Biggar SR et al. (1996a). Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J 15: 5370–5382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR . (1996b). Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev 10: 2117–2130.

    Article  CAS  PubMed  Google Scholar 

  • Wong AK, Shanahan F, Chen Y, Lian L, Ha P, Hendricks K et al. (2000). BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res 60: 6171–6177.

    CAS  PubMed  Google Scholar 

  • Yamamichi N, Inada K, Ichinose M, Yamamichi-Nishina M, Mizutani T, Watanabe H et al. (2007). Frequent loss of Brm expression in gastric cancer correlates with histologic features and differentiation state. Cancer Res 67: 10727–10735.

    Article  CAS  PubMed  Google Scholar 

  • Yamamichi N, Yamamichi-Nishina M, Mizutani T, Watanabe H, Minoguchi S, Kobayashi N et al. (2005). The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential. Oncogene 24: 5471–5481.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Author notes

  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

Authors
  1. S Gramling
    View author publications

    Search author on:PubMed Google Scholar

  2. C Rogers
    View author publications

    Search author on:PubMed Google Scholar

  3. G Liu
    View author publications

    Search author on:PubMed Google Scholar

  4. D Reisman
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to D Reisman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/onc.2011.80

Keywords

This article is cited by

Search

Advanced search

Quick links