Taming the Master:SWI/SNF Chromatin Remodeller as a Therapeutic Target in Cancer

Eukaryotic cells use histone modifiers and chromatin remodellers to facilitate protein DNA interactions in the nucleus; an important requisite for regulating several cardinal nuclear processes including transcription, replication, DNA repair and recombination, etc. The SWI/SNF complex is the most well-studied chromatin remodeller and is conserved from yeast to mammals. The complex is recruited to specific DNA sites, where it uses energy from ATP hydrolysis to catalyse nucleosome sliding or histone eviction from DNA. Mutational inactivation of SWI/SNF components has been identified in neurological syndromes and in several cancers. Recent deep sequencing studies have revealed a SWI/SNF mutation frequency of 20% in cancer genomes. In addition to mutations in tumour samples, extensive studies on cell lines and animal models have revealed tumour suppressive features for many individual SWI/SNF components. Thus, components of the complex are classified as tumour suppressors. Interestingly, however, majority of mutations cause incomplete inactivation of the complex, leaving behind a ‘residual’ complex that can be targeted for therapy. In addition, characterization of multiple roles of SWI/SNF components has revealed several therapeutic options. The current review summarizes the multi-faceted therapeutic opportunities for tumour bearing mutations in genes, encoding SWI/SNF components.