Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities

Abstract

Introduction:Cancer genome sequencing studies have discovered mutations in members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex in nearly 25% of human cancers. The SWI/SNF complex, first discovered in S. cerevisiae, shows strong conservation from yeast to Drosophila to mammals, contains approximately 10-12 subunits and regulates nucleosome positioning through the energy generated by its ATPase subunits. The unexpected finding of frequent mutations in the complex has fueled studies to identify the mechanisms that drive tumor development and the accompanying therapeutic vulnerabilities. Areas covered:In the review, we focus upon the potential roles different SWI/SNF subunit mutations play in human oncogenesis, their common and unique mechanisms of transformation and the potential for translating these mechanisms into targeted therapies for SWI/SNF-mutant tumors.

BRG1 Activates Proliferation and Transcription of Cell Cycle-Dependent Genes in Breast Cancer Cells

“…The SWI/SNF chromatin remodeling complex has attracted increasing attention, particularly in cancer biology due to mutations, deletions and insertions in BRG1, and in some of the SWI/SNF core subunits (e.g., SNF5, ARID1A) in~20% of human tumors. Mutations associated with gain and loss of function, as well as fluctuation in the expression of SWI/SNF components, are linked to the occurrence of cancer and its progression in several ways [15,16]. BRG1 was initially considered as a tumor suppressor, based on, for example, premises from mouse model of primary cells, where inactivation of Brg1 and Snf5 leads to an overall decrease in nucleosome occupancy at a large number of promoters, products of which potentiate cell proliferation [17].…”

“…Due to a similar degree of repression of BRG1-dependent genes by EP300 inhibition (Figure 2A-D), such an option extends the possibility of gene targeting by a wider range of compounds. Notably, BRG1 (and perhaps EP300) inhibition might be considered as a therapeutic strategy in other cancer types because BRG1 is overexpressed in other tumor types, although limited insights into how different SWI/SNF subunits drive the development of tumors and complex nature of contribution to defining specific oncogenic pathways clearly requires further investigation [15].…”

Udział kompleksów SWI/SNF opartych na aktywności BRG1 w determinowaniu fenotypu komórek nowotworowych

“…Zmiana polega przeważnie na obniżeniu poziomu BRM. Występuje ona zwykle w nowotworach łagodnych i charakteryzujących się dobrym rokowaniem [21,23].…”

“…Kolejną podjednostką SWI/SNF, której aberracje predysponują do rozwoju nowotworów, jest ARID1A. Podobnie jak w przypadku BRG1, mutacje tego genu obserwowane są w wielu typach nowotworów, ale najczęściej (bo aż w 50% przypadków) dotyczą jasnokomórkowego raka jajnika, a utrata ARID1A może być jednym z pierwszych etapów jego rozwoju [23,24]. Wykazano także, że spadek poziomu ARI-D1A pogarsza rokowanie pacjentów z nowotworami piersi [25].…”

“…Mutacje w obrębie SNF5 są obecne w 95% guzów rabdoidalnych -typowych dla wieku dziecięcego, które pojawiają się najczęściej w obrębie nerek i ośrodkowego układu nerwowego. W tych nowotworach mutacje genu kodującego SNF5 powodują najczęściej jego zanik w komórce [23]. Mutacje genu PBRM1 obniżają lub całkowicie wyciszają jego ekspresję.…”