BRD9-p53-E2F1 circuit orchestrates cell growth and DNA damage repair in gastric cancer
Qingqing Zhou, Qi Wang, Yantao Duan, Chi Zhang, Tengfei Liu, Hengrui Liu, Mindi Zhao, Zhihuang Hu
Abstract
BACKGROUND: BRD9 is involved in multiple physiological and pathological pathways, yet its functional role and molecular mechanisms in gastric cancer (GC) remain largely unexplored. Addressing this knowledge gap is critical given the persistent global mortality burden of GC and the limited efficacy of current therapeutic strategies. METHODS: BRD9 expression in GC patients was systematically analyzed using immunohistochemical (IHC) assays and transcriptomic datasets. Comprehensive functional validation, employing cellular and murine tumor models, elucidated BRD9's role in GC progression. Molecular pathways underlying BRD9-mediated gastric carcinogenesis were delineated through integrated approaches, including RNA sequencing, co-immunoprecipitation (co-IP), subcellular fractionation, and luciferase reporter assays. RESULTS: BRD9 was significantly overexpressed in GC and associated with poor patient prognosis. Functionally, BRD9 promoted GC cell proliferation and enhanced DNA damage repair capacity. Mechanistically, elevated BRD9 expression inhibited p53 nuclear translocation via direct binding, subsequently activating the E2F transcription factor family. Notably, we identified that E2F1 directly bound to and transactivated the BRD9 promoter, establishing a positive feedback loop that sustains BRD9 expression. Additionally, BRD9 knockdown sensitized GC cells to cisplatin and oxaliplatin treatment. CONCLUSIONS: These findings highlight the critical role of BRD9 in GC progression and its therapeutic potential. The BRD9-p53-E2F1 axis acts as a crucial regulator of GC cell proliferation and DNA damage response. Targeting BRD9 pharmacologically could be a novel therapeutic approach to enhance chemotherapy efficacy and improve treatment outcomes in GC patients.