EWS-FLI1 modulated alternative splicing of ARID1A reveals novel oncogenic function through the BAF complex

There is a long-established connection between epigenetic reprogramming and the local function of the spliceosome. Recently the oncogenic potential of this connection has also been recognized. Recent work has demonstrated that EWS-FLI1 recruits the BRG1/BRM-associated factor (BAF) complex, however, the specific BAF subunits that interact with EWS-FLI1 and the role of the BAF complex in oncogenesis remains unknown. Within the BAF complex, the AT-rich interactive domain-containing protein 1A (ARID1A, BAF250a) gene encodes a central scaffold. EWS-FLI1 is a well-described transcriptional regulator that also has a role in modulating RNA splicing. While EWS-FLI1 alters the splicing of many mRNA isoforms, the role of splicing modulation in ES oncogenesis remains unknown. Here we report a direct connection between the EWS-FLI1-induced transcriptome and the EWS-FLI1 protein interactome to reveal a novel interaction with a specific isoform of ARID1A that has a direct impact on oncogenicity. We report a novel feed-forward cycle of EWS-FLI1 and ARID1A-L facilitating ES growth through splicing modulation and protein stability that may lead to improved cancer-specific drug targeting.