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

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• Methylation of proteins, particularly arginine methylation, is a key regulator of cellular functions.
• AKT1 protein methylation at arginine-391 (R391) has been identified, but its specific reader protein remains unknown.
• Bromodomain-containing protein 9 (BRD9) is known as a reader of acetylated lysine.

Purpose of the Study:

• To identify the reader protein for AKT1 methylation at R391.
• To investigate the functional role of BRD9 in AKT1 signaling and tumorigenesis.
• To explore the therapeutic potential of targeting BRD9 and EZH2 in cancer.

Main Methods:

• Biochemical assays to characterize protein-protein interactions.
• RNA sequencing to analyze transcriptional changes.
• In vitro and in vivo cancer models to assess tumor growth and proliferation.

Main Results:

• BRD9 unexpectedly recognizes methylated R391 of AKT1 via its bromodomain.
• Disruption of BRD9's methylarginine reader function inhibits AKT activation and tumorigenesis.
• BRD9 and AKT coregulate a transcriptional program involving enhancer of zeste homolog 2 (EZH2) and histone-3 lysine-27 methylation.
• Combined inhibition of BRD9 and EZH2 shows synergistic effects on suppressing cancer cell proliferation and tumor growth.

Conclusions:

• BRD9 possesses a novel methylarginine reader function for AKT1.
• Targeting BRD9 offers a potential therapeutic strategy for cancer.
• Combination therapy with BRD9 and EZH2 inhibitors demonstrates significant anti-tumor effects.