BRD9 functions as a methylarginine reader to regulate AKT-EZH2 signaling

Arginine methylation is a common posttranslational modification that is catalyzed by a family of protein arginine methyltransferases. Recognition of methylarginine marks by effector proteins (“readers”) is a critical link between arginine methylation and various cellular processes. We recently identified methylation of AKT1 at Arg391 by PRMT5, but the reader for this methylation has yet to be characterized. Here, we show that BRD9, a reader of acetylated lysine, unexpectedly recognizes Arg391-methylated AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA-sequencing data shows that BRD9 and AKT co-regulate a hallmark transcriptional program in part through EZH2-mediated H3K27 trimethylation. Lastly, we find that inhibitors of BRD9 and EZH2 display synergistic effects on inhibition of cell viability and tumor growth. Together, our study demonstrates that BRD9 serves as a methylarginine reader to promote AKT-EZH2 oncogenic signaling and combined inhibition of BRD9 and EZH2 is a potential strategy for cancer therapy.