1. ¹Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA
2. ²Expression Génétique et Maladies, URA1644 du CNRS, Département de Biologie du Développement, Institut Pasteur, Bât. Fernbach, Rue du Docteur Roux, Paris Cedex, France
3. ³Department of Pathology, University of Michigan, Ann Arbor, MI, USA

Correspondence: Dr D Reisman, Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, MRSB2 B570B, Ann Arbor, MI 48103-0686, USA. E-mail: dreisman@umich.edu

Received 21 November 2006; Revised 2 April 2007; Accepted 2 April 2007; Published online 4 June 2007.

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.