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

Recognition of methylarginine marks by effector proteins ("readers") is a critical link between arginine methylation and various cellular processes. Recently, we identified methylation of AKT1 at arginine-391 (R391), but the reader for this methylation has yet to be characterized. Here, we show that bromodomain-containing protein 9 (BRD9), a reader of acetylated lysine, unexpectedly recognizes methylated R391 of AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA sequencing data show that BRD9 and AKT coregulate a hallmark transcriptional program in part through enhancer of zeste homolog 2 (EZH2)-mediated methylation of histone-3 lysine-27. We also find that inhibitors of BRD9 and EZH2 display synergistic effects on suppression of cell proliferation and tumor growth. Collectively, our study reveals a previously unknown function of BRD9 and a potential therapeutic strategy for cancer treatment by combining BRD9 and EZH2 inhibitors.