title: Control of NF-kB activity in human melanoma by bromodomain and extra-terminal protein inhibitor I-BET151.
abstract: 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.
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Gallagher
authors.forename: Branka
authors.initials: B
authors.lastname: Mijatov
authors.forename: Dilini
authors.initials: D
authors.lastname: Gunatilake
authors.forename: Kavitha
authors.initials: K
authors.lastname: Gowrishankar
authors.forename: Jessamy
authors.initials: J
authors.lastname: Tiffen
authors.forename: Wilmott
authors.initials: W
authors.lastname: James
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Gulietta
authors.initials: G
authors.lastname: Pupo
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
chemical_list: D018925:Chemokines; D006576:Heterocyclic Compounds, 4 or More Rings; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A
keywords: NF-kappaB; bromodomain and extra-terminal; cancer; chemokine; cytokine; melanoma