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

Stuart J. Gallagher*, Branka Mijatov, Dilini Gunatilake, Kavitha Gowrishankar, Jessamy Tiffen, Wilmott James, Lei Jin, Gulietta Pupo, Carleen Cullinane, Grant A. Mcarthur, Peter J. Tummino, Helen Rizos, Peter Hersey

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)


The transcription factor NF-kappaB (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-BET151 to inhibit NF-kB in melanoma cells. We show that I-BET151 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 BRD2 is the main BET protein involved in regulation of NF-kB and that I-BET151 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.

Original languageEnglish
Pages (from-to)1126-1137
Number of pages12
JournalPigment Cell and Melanoma Research
Issue number6
Publication statusPublished - 1 Nov 2014
Externally publishedYes


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