SWI / SNF Chromatin Remodelling and Human Cancer

Abstract

Brahma (BRM) and Brahma‐related gene 1 (BRG1) are two mutually exclusively catalytic subunits of the switch in mating type/sucrose nonfermenting complex. These two key anticancer proteins are frequently targeted and silenced during cancer development. The anticancer function of BRM can be abrogated when it becomes acetylated or when it is epigenetically silenced. Central to BRM silencing is the presence of two inherited insertional polymorphisms within the BRM promoter that are statistically linked to cancer risk. Both BRM acetylation and silencing can be reversed by a number of compound families and might be important to how flavonoids and NSAIDS inhibit cancer. While BRG1 is very frequently mutated in most human cancers, it is more commonly inactivated by aberrant splicing and by an AKT‐pathway‐mediated‐translation block. While BRG1 and BRM are tied to deoxyribonucleic acid repair, growth control, differentiation, development, as well as epithelial–mesenchymal transition and are estimated to regulate 4–8% of the human genome, the inactivation of either protein is only modestly tumourigenic. This occurs in part because BRG1 and BRM are functionally redundant, which blunts the tumourigenic effect when only one gene is aberrantly silenced. Further insights into the mechanisms that regulate these genes may lead to novel therapeutic strategies that may reverse the silencing of these two important anticancer genes. Key Concepts Reversal of the epigenetic silencing of a gene may serve as a basis for drug therapy. Anticancer genes are epigenetically regulated by insertional polymorphisms. The functional redundancy of BRG1 and BRM thwarts cancer development. Post‐translational modification of BRM and BRG1 alters the cellular roles of these proteins from growth inhibitors to growth promoters. The loss of cofactors (i.e. BRG1 and/or BRM) for RB‐mediated‐growth inhibition could preclude the function of CDK inhibitors used clinically. Specific SWI/SNF subunits are commonly mutated and inactivated in specific cancer types. Diminished SWI/SNF activity, but not the complete abrogation of function, is tumourigenic.