Targeting Bromodomain-Containing Protein 9 in Human Uterine Fibroid Cells

Bromodomain (BRD)-containing proteins are evolutionarily conserved protein-protein interaction modules involved in many biological processes. BRDs selectively recognize and bind to acetylated lysine residues, particularly in histones, and thereby have a crucial role in the regulation of gene expression. BRD protein dysfunction has been linked to many diseases, including tumorigenesis. Previously, we reported the critical role of BRD-containing protein 9 (BRD9) in the pathogenesis of UFs. The present study aimed to extend our previous finding and further understand the role of the BRD9 in UFs. Our studies demonstrated that targeted inhibition of BRD9 with its potent inhibitor TP-472 inhibited the pathogenesis of UF through increased apoptosis and proliferation arrest and decreased extracellular matrix deposition in UF cells. High-throughput transcriptomic analysis further and extensively demonstrated that targeted inhibition of BRD9 by TP-472 impacted the biological pathways, including cell cycle progression, inflammatory response, E2F targets, ECM deposition, and m⁶A reprogramming. Compared with the previous study, we identified common enriched pathways induced by two BRD9 inhibitors, I-BRD9 and TP-472. Taken together, our studies further revealed the critical role of BRD9 in UF cells. We characterized the link between BRD9 and other vital pathways, as well as the connection between epigenetic and epitranscriptome involved in UF progression. Targeted inhibition of BRD proteins might provide a non-hormonal treatment strategy for this most common benign tumor in women of reproductive age.