BRD9 Inhibition by Natural Polyphenols Targets DNA Damage/Repair and Apoptosis in Human Colon Cancer Cells

Epigenetic mechanisms play an important role in the etiology of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions. Inhibitors of the bromodomain and extraterminal (BET) family have entered into clinical trials as anticancer agents, and interest has grown in other acetyl 'reader' proteins as therapeutic targets, including non-BET member bromodomain-containing protein 9 (BRD9). We report here that overexpression of BRD9 is associated with poor prognosis in CRC patients, and that siRNA-mediated knockdown of BRD9 decreased cell viability and activated apoptosis in human colon cancer cells, coincident with increased DNA damage. Seeking natural compounds as BRD9 antagonists, molecular docking in silico identified several polyphenols such as Epigallocatechin-3-gallate (EGCG), Equol, Quercetin, and Aspalathin, with favorable binding energies, supported by BROMOscan (R) (DiscoverX) and isothermal titration calorimetry experiments. Polyphenols mimicked BRD9 knockdown and iBRD9 treatment in reducing colon cancer cell viability, inhibiting colony formation, and enhancing DNA damage and apoptosis. Normal colonic epithelial cells were unaffected, signifying cancer-specific effects. These findings suggest that natural polyphenols recognize and target BRD9 for inhibition, and might serve as useful lead compounds for bromodomain therapeutics in the clinical setting.

Automated summary

Epigenetic mechanisms, specifically the deregulation of bromodomain (BRD) functions, play a significant role in colorectal cancer (CRC) and other malignancies. This study shows that overexpression of BRD9 is associated with poor prognostic outcomes in CRC patients. Natural polyphenols such as Epigallocatechin-3-gallate (EGCG), Equol, Quercetin, and Aspalathin were identified as potential BRD9 antagonists, as they reduced colon cancer cell viability, inhibited colony formation, and increased DNA damage and apoptosis.