title: Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells.
abstract: Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in tumor development and progression. The transcriptional coactivator p300/CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of p300/CBP HAT activity, C646, in order to evaluate the functional contributions of p300/CBP HAT to tumor development and progression. Here we report that C646 inhibits the growth of human melanoma and other tumor cells and promotes cellular senescence. Global assessment of the p300 HAT transcriptome in human melanoma identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of melanoma cells after combination treatment with cisplatin. Together, our data suggest that p300 HAT activity mediates critical growth regulatory pathways in tumor cells and may serve as a potential therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents that are currently ineffective against specific cancers.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Gai
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Eller
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Elm
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Cecilia A
authors.initials: CA
authors.lastname: Larocca
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Byungwoo
authors.initials: B
authors.lastname: Ryu
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Izabela P
authors.initials: IP
authors.lastname: Panova
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Beverley M
authors.initials: BM
authors.lastname: Dancy
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Bowers
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Meyers
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lareau
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: pcole@jhmi.edu.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: staverna@jhmi.edu.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Taverna
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: alani@bu.edu.
authors.forename: Rhoda M
authors.initials: RM
authors.lastname: Alani
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D009578:Nitrobenzenes; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D001565:Benzoates; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D009578:Nitrobenzenes; D011720:Pyrazoles; D047069:Pyrazolones; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C584509:4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid