Bromodomain of CREBBP/EP300 cooperates with BNC2 to reprogram cell state in breast cancer

ABSTRACT: The plasticity of cancer cells influences their phenotypic and functional diversity. Understanding the mechanisms underlying cell state transitions, particularly the epithelial-mesenchymal transition (EMT) and its reverse process – mesenchymal-epithelial transition (MET), can provide insights into therapeutic strategies that control tumor progression and metastasis. Epigenetic reprogramming governs cellular plasticity. To survey epigenetic inhibitors capable of inducing MET, we employ a high-throughput small-molecule library screen coupled to a cell state reporter assay. We identify CREBBP/EP300 bromodomain inhibitor as a potent MET promoter, which specifically induces cell state transition in basal-like breast cancer but not luminal breast cancer. CREBBP/EP300 bromodomain inhibition leads to a gain in luminal characteristics and a reduction in stem-like properties. Strikingly, inhibiting the bromodomain of CREBBP/EP300, rather than its HAT domain, is more effective in promoting MET, decreasing tumorigenicity, and impeding metastasis. This underscores the finding that CREBBP/EP300 mediated cell state reprogramming is not attributed to changes in histone acetylation but likely converges on effector genes recognized by the bromodomain. Through transcriptomic and ChIP-Seq analyses, we find the zinc finger protein basonuclin-2 (BNC2) as a potential transcription factor involved in cell state regulation. Its interaction with CREBBP/EP300 bromodomain is essential for regulating super-enhancer-associated genes that maintain the mesenchymal cell state. These findings provide a new functional role for the bromodomain in epigenetic regulation and suggest strategies for therapeutic intervention in mesenchymal breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276326 | GEO | 2025/09/30

REPOSITORIES: GEO