PBRM1-Dependent PBAF Targeting is Required for EMT and Metastasis in Breast Cancer.

SWI/SNF chromatin remodelers utilize ATP to mobilize nucleosomes on DNA and are represented by three biochemically distinct subcomplexes, the more abundant cBAF and the less abundant PBAF and GBAF subcomplexes. Patient mutations and genetic studies have identified important roles for PBAF subunits in development and disease; however, relating PBAF-mediated phenotypes to biochemical function in chromatin regulation and gene expression has been challenging. Further complicating matters, cell-based systems often do not reflect the phenotypes and genotypes observed with PBAF mutations in vivo . Here we show that the PBRM1 subunit of PBAF is critical for the completion of TGFB1-mediated epithelial-mesenchymal transition of mammary cells in vitro as well as the metastasis of murine breast cancers in vivo. Using epigenomics to profile different stages of EMT, we find that PBRM1 is necessary for targeting PBAF to inducible promoters marked by H3K14ac alone. We further find that PBRM1 facilitates DNA accessibility at sites bound by TGFβ1-inducible transcription factors, such as Atf3, for the induction of genes involved in migration, cell survival, and inflammation. Our model allows us to separate constitutive vs inducible gene expression to help explain some of the context-dependent phenotypes observed with PBRM1 deletion. In addition, we provide evidence that while PBRM1 deletions can promote the initiation of certain cancers in early stages, PBAF may be a vulnerability in late-stage metastatic cancers.