BET bromodomain inhibition potentiates ocular melanoma therapy by inducing cell cycle arrest
Ocular melanoma is a common primary malignant ocular tumor in adults with limited effective treatments, so novel therapeutic approaches are desperately needed. Epigenetic regulation plays an important role in tumor development. The SWI/SNF chromatin remodeling complex and bromodomain and extraterminal domain (BET) family proteins are epigenetic regulators involved in several cancers. We aimed to screen a candidate small molecule inhibitor targeting the SWI/SNF complex or BET proteins and investigate its effect and mechanism in ocular melanoma. Colony formation assays were applied to select the most effective candidate inhibitor (JQ-1). We observed phenotypes caused by knockdown of the corresponding gene and synergistic effects with BRD inhibitor (BRDi) treatment and SWI/SNF complex knockdown. We further validated the efficacy of JQ-1 in 10 ocular melanoma cell lines and a mouse xenograft model. The effect of JQ-1 on ocular melanoma cell cycle and apoptosis was analyzed with flow cytometry. We performed RNA sequencing in 2 pairs of ocular melanoma cell lines treated with JQ-1 and control cells treated with DMSO. Gene set enrichment analysis (GSEA) was performed for pathway analysis of the differentially expressed genes (DEGs). We also validated the correlations of DEGs with BRD4 and patient outcomes. Overall, JQ-1 may act downstream of BRD4 and suppress ocular melanoma growth by inducing G1 cell cycle arrest. Overall design: We then performed gene expression profiling analysis using data obtained from RNA-seq of cells (MEL270 and MEL290) treated with JQ-1 (0.04 µM) or DMSO at two times.