Bromodomain of CREBBP/EP300 cooperates with BNC2 to reprogram cell state in breast cancer
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. Overall design: To evaluate the transcriptional reprogramming that could be respobsible for mesenchymal-epithelial transitions, we treated NAMEC8 cells with SGC-CBP30 and A-485. We then performed gene expression profiling analysis using data obtained from RNA-seq of NAMEC8 that has been treated with SGC-CBP30 and A-485 for seven days in duplicates. Comparative gene expression profiling analysis of RNA-seq data for NAMEC8 treated with DMSO and SGC-CBP30, as well as DMSO and A-485, were done.