Targeting of the SWI/SNF chromatin remodeling complex in cancer therapy

Abstract

Chromatin remodeling is the one of the main epigenetic ways of gene expression regulation both in normal cells and in oncological diseases. Genes encoding protein subunits of SWI/ SNF remodeling complexes often mutate and/or change their expression in human tumors, affecting the expression programs of many genes during carcinogenesis, which is associated with the occurrence and progression of cancer. Today, there are no therapeutic drugs that could directly change the structure of chromatin because of complexity of this process with involvement of a large number of genes, proteins, non-coding transcripts and other intermediary molecules. However, the chromatin remodeling complexes can be affected by consistent influence on the subunits and the genes encoding them, as well as the non-coding RNAs that regulate the operation of these complexes and direct them to the target gene regions. Today, several successful strategies have been proposed to influence epigenetic regulators associated with chromatin in order to cause synthetic lethality of cancer cells and block tumor growth. To influence the processes of chromatin remodeling, various strategies and mechanisms are being investigated, from inhibitors of bromodomains of individual subunits to direct effects on the function of SWI/ SNF by destroying its main adenosine triphosphatase subunit. In our review, we analyze the ways and mechanisms of influencing the SWI/ SNF chromatin remodeling complex in order to obtain a stable antitumor effect, from experiments on tumor cells and animal models to the combined use of clinical drugs for the treatment of cancer patients.

Keywords

• chromatin remodeling
• swi/ snf
• somatic mutations
• synthetic lethality of cancer cells
• bromodomain inhibitors