TY - JOUR
T1 - Control of NF-kB activity in human melanoma by bromodomain and extra-terminal protein inhibitor I-BET151
AU - Gallagher, Stuart J.
AU - Mijatov, Branka
AU - Gunatilake, Dilini
AU - Gowrishankar, Kavitha
AU - Tiffen, Jessamy
AU - James, Wilmott
AU - Jin, Lei
AU - Pupo, Gulietta
AU - Cullinane, Carleen
AU - Mcarthur, Grant A.
AU - Tummino, Peter J.
AU - Rizos, Helen
AU - Hersey, Peter
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84913607582&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/633004
U2 - 10.1111/pcmr.12282
DO - 10.1111/pcmr.12282
M3 - Article
C2 - 24924589
AN - SCOPUS:84913607582
SN - 1755-1471
VL - 27
SP - 1126
EP - 1137
JO - Pigment Cell and Melanoma Research
JF - Pigment Cell and Melanoma Research
IS - 6
ER -