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.

Keywords: epigenetic silencing; tumour susceptibility gene; polymorphism; cancer risk; chromatin remodelling complex; translational block

Figure 1. This figure shows the process by which the chromatin marks within a DNA domain (gene) change from methylation to acetylation, which denotes open chromatin, when genes can be expressed. SWI/SNF subunits are known to contain bromodomains, which target and bind to acetylated histones; this is thought to help recruit SWI/SNF to areas in which the chromatin needs to be opened.
Figure 2. This figure illustrates the composition of the three delineated SWI/SNF complexes that differ according to which ATPase catalytic subunit (BRG1 or BRM) is present and according to the second subunit that is present: either BAF250 (ARID1A or ARID1B) or BAF180 (PBRM1).
Figure 3. This figure shows the position and composition of the BRM polymorphisms within the BRM promoter. Polymorphism 741 is composed of a triplicate 7 base pair sequence ‘TATTTTT,’ while the nonpolymorphic sequence (wild‐type) contains only a duplicate of this sequence. Similarly, polymorphism 1321 is composed of a duplicate 6 base pair sequence ‘TTTTAA’, while the wild‐type sequence contains this sequence only once.
Figure 4. This figure illustrates how the two transcription factors GATA3 and MEF2D recruit HDACs (HDAC3 and HDAC9) to the BRM polymorphisms, which leads to the silencing of BRM by this complex of proteins. GATA3 and MEF2D drive HDAC9 overexpression, which is part of the mechanism that drives BRM silencing.
Figure 5. This figure shows the conversion of BRM to acetylated‐BRM as a function of HDAC2, which removes acetyl groups from BRM, and KAT2B and KAT8, which induce BRM acetylation. This diagram shows the four specific lysine residues that are known to be acetylated and that drive the change in BRM function. The deacetylated form of BRM interacts with tumour suppressors such as RB to inhibit growth, while the acetylated form of BRM interacts with oncogenes to drive growth.
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Reisman, David, Thompson, Kenneth, Marquez‐Vilendrer, Stefanie, and Lu, Li(Jul 2016) SWI/SNF Chromatin Remodelling and Human Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025738]