(mis)-Targeting of SWI/SNF complex(es) in cancer

Abstract

The ATP-dependent chromatin remodeling complex SWI/SNF (also called BAF) is critical for the regulation of gene expression. During the evolution from yeast to mammals, the BAF complex has evolved an enormous complexity that contains a high number of subunits encoded by various genes. Emerging studies highlight the frequent involvement of altered mammalian SWI/SNF chromatin-remodeling complexes in human cancers. Here, we discuss the recent advances in determining the structure of SWI/SNF complexes, highlight the mechanisms by which mutations affecting these complexes promote cancer, and describe the promising emerging opportunities for targeted therapies.

Keywords: BAF complex; Chromatin remodeling; Epigenetics; Inhibitors; Mutations; Therapy.

Fig. 1

Mode of binding of SWI/SNF complex to nucleosome. Cartoon illustrating the binding of canonical BAF (cBAF) (a) and polybromo-associated BAF (PBAF) (b) with nucleosome core particle (NCP). The distinct modules are marked in distinct colors: blue for ATPase, green for ARP, and orange for base modules. Also, the unique subunits within the base modules are highlighted in darker orange color. PBAF complex uniquely contains a histone binding lobe which enables its interaction with modified histone tails in the NCP

Fig. 2

Mutational frequencies of SWI/SNF components in cancer. a Percentage of mutated samples for each SWI/SNF subunit was plotted by mining the data from two cancer datasets—Pan-Cancer Analysis of Whole Genomes and China pan-cancer dataset (N = 13,116) from The Cancer Genome Atlas (TCGA). The graph distinguishes various complex specific and shared subunits between cBAF, PBAF, and ncBAF complexes. b Heatmap of the frequency of a few frequently mutated subunits across various cancer types. The TCGA data set (N = 13,116) was used to generate the heatmap. The map also depicts that ARID1A is frequently mutated in various cancers, while PBRM1 is most mutated in renal cell carcinoma