On Sept. 7, 2020, research from the Children’s Medical Center Research Institute at UT Southwestern (CRI) determined how mutations in two key SWI/SNF proteins, ARID1A and ARID1B, can drive cancer development by disrupting the assembly of SWI/SNF complexes. The study, published in Nature Cancer, addressed fundamental questions about SWI/SNF biology as well as therapeutic strategies designed to kill cancer cells by targeting this complex.

SWI/SNF protein complexes help to pack and unpack DNA in the genome and are composed of 10-15 interacting proteins that can be arranged into different configurations in different tissues. Three main types of SWI/SNF complexes have been identified: cBAF, pBAF and ncBAF. But the roles they play in tissue development and disease have been unclear. To understand the importance of these complexes in animals, researchers at CRI focused on the cBAF complex. This complex was chosen because it is the most abundant one, and a subunit unique to this complex, ARID1A, is one of the most mutated genes in human cancer. 

ARID1A is closely related to another protein known as ARID1B, which is also unique to cBAF. It has been shown that some cancer cells need at least one ARID1 protein to survive. To examine whether simultaneous loss of both ARID1A and ARID1B would be more likely to cause or kill cancer cells, researchers eliminated or knocked out both genes in mice. Strikingly, the loss of both ARID1A and ARID1B genes resulted in aggressive liver and skin cancer formation within weeks.