Control of NF‐kB activity in human melanoma by bromodomain and extra‐terminal protein inhibitor I‐BET151

Summary The transcription factor NF ‐kappa B ( NF ‐ kB ) is a key regulator of cytokine and chemokine production in melanoma and is responsible for symptoms such as anorexia, fatigue, and weight loss. In addition, NF ‐ kB is believed to contribute to progression of the disease by upregulation of cell cycle and anti‐apoptotic genes and to contribute to resistance against targeted therapies and immunotherapy. In this study, we have examined the ability of the bromodomain and extra‐terminal ( BET ) protein inhibitor I ‐ BET 151 to inhibit NF ‐ kB in melanoma cells. We show that I ‐ BET 151 is a potent, selective inhibitor of a number of NF ‐ kB target genes involved in induction of inflammation and cell cycle regulation and downregulates production of cytokines such as IL ‐6 and IL ‐8. SiRNA studies indicate that BRD 2 is the main BET protein involved in regulation of NF ‐ kB and that I ‐ BET 151 caused transcriptional downregulation of the NF ‐ kB subunit p105/p50. These results suggest that BET inhibitors may have an important role in treatment of melanoma where activation of NF ‐ kB may have a key pathogenic role.