title: The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells.
abstract: Epigenetic changes are widespread in melanoma and contribute to the pathogenic biology of this disease. In the present study, we show that I-BET151, which belongs to a new class of drugs that target the BET family of epigenetic "reader" proteins, inhibits melanoma growth in vivo and induced variable degrees of apoptosis in a panel of melanoma cells. Apoptosis was caspase dependent and associated with G1 cell cycle arrest. All melanoma cells tested had increased levels of the BH3 proapoptotic protein BIM, which appeared to be regulated by the BRD2 BET protein and to some extent by BRD3. In contrast, knockdown experiments indicated that inhibition of BRD4 was associated with decreased levels of BIM. Apoptosis was dependent on BIM in some but not all cell lines, indicating that other factors were determinants of apoptosis, such as downregulation of antiapoptotic proteins revealed in gene expression arrays. G1 cell cycle arrest appeared to be mediated by p21 and resulted from inhibition of the BRD4 protein. The activity of BET protein inhibitors appears independent of the BRAF and NRAS mutational status of melanoma, and further studies to assess their therapeutic role in melanoma are warranted.
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Gallagher
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Branka
authors.initials: B
authors.lastname: Mijatov
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Dilini
authors.initials: D
authors.lastname: Gunatilake
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Jessamy C
authors.initials: JC
authors.lastname: Tiffen
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Gowrishankar
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.affiliation: Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: Epinova Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Epinova Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Smithers
authors.affiliation: Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.affiliation: Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia; Melanoma Institute of Australia, North Sydney, New South Wales, Australia. Electronic address: peter.hersey@sydney.edu.au.
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D000092468:Bromodomain Containing Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D020169:Caspases; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020558:GTP Phosphohydrolases; D006576:Heterocyclic Compounds, 4 or More Rings; D008565:Membrane Proteins; D020559:Monomeric GTP-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D014157:Transcription Factors; C000606775:BCL2L11 protein, human; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000606776:Bcl2l11 protein, mouse; C493956:CDKN1A protein, human; C568713:GSK1210151A; C482119:BRAF protein, human; C579846:NRAS protein, human; C586503:Nras protein, mouse