PAX8 interacts with the SWI/SNF complex at enhancers to drive proliferation in ovarian cancer.

Abstract

Activation of lineage-specific gene expression programs is mediated by recruitment of lineage-specific transcription factors and their coactivators to chromatin. The lineage factor PAX8 drives essential gene expression in ovarian cancer cells and is required for tumor proliferation. However, the molecular details surrounding co-factor recruitment and specific activation of transcription by PAX8 remain unknown. Here, we identify an important functional interaction between PAX8 and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. We show that PAX8 can recruit SWI/SNF complexes to DNA, where they function to open chromatin and facilitate expression of PAX8 target genes. Genetic deletion of PAX8 results in loss of SWI/SNF from PAX8 bound enhancers, loss of expression of associated target genes, and reduced proliferation. These results can be phenocopied by pharmacological inhibition of SWI/SNF ATPase activity. These data indicate that PAX8 mediates the expression of an essential ovarian cancer proliferative program in part by the recruitment of the SWI/SNF complex, highlighting a novel vulnerability in PAX8 dependent ovarian cancer. Implications: PAX8 recruits SWI/SNF complexes to enhancers, to mediate expression of genes essential for ovarian cancer proliferation.