title: The identification of a novel natural activator of p300 histone acetyltranferase provides new insights into the modulation mechanism of this enzyme.
abstract: Many severe human pathologies are related to alterations of the fine balance between histone acetylation and deacetylation; because not all such diseases involve hypoacetylation, but also hyperacetylation, compounds able to enhance or repress the activities of histone acetyltransferases (HATs) could be promising therapeutic agents. We evaluated in vitro and in cell the ability of eleven natural polyisoprenylated benzophenone derivatives to modulate the HAT activity of p300/CBP, an enzyme that plays a pivotal role in a variety of cellular processes. Some of the tested compounds bound efficiently to the p300/CBP protein: in particular, guttiferone A, guttiferone E and clusianone inhibit its HAT activity, whereas nemorosone showed a surprising ability to activate the enzyme. The ability of nemorosone to penetrate cell membranes and modulate histone acetylation into the cell together with its high affinity for the p300/CBP enzyme made this compound a suitable lead for the design of optimized anticancer drugs. Besides, the studies performed at a cellular and molecular level on both the inhibitors and the activator provided new insights into the modulation mechanism of p300/CBP by small molecules.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo 1, 84084 Fisciano, SA, Italy. fdalpiz@unisa.it
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Dal Piaz
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tosco
authors.forename: Daniela
authors.initials: D
authors.lastname: Eletto
authors.forename: Anna L
authors.initials: AL
authors.lastname: Piccinelli
authors.forename: Ornella
authors.initials: O
authors.lastname: Moltedo
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschelli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
authors.forename: Paolo
authors.initials: P
authors.lastname: Remondelli
authors.forename: Luca
authors.initials: L
authors.lastname: Rastrelli
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Nunziatina
authors.initials: N
authors.lastname: De Tommasi
mesh_terms: D000107:Acetylation; D001577:Benzophenones / Q000737:chemistry* / Q000494:pharmacology; D016227:Benzoquinones; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D013816:Thermodynamics; D050880:p300-CBP Transcription Factors / Q000819:agonists* / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D001577:Benzophenones; D016227:Benzoquinones; D001643:Bridged Bicyclo Compounds; D006657:Histones; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C118110:7-epiclusianone; C121576:polyisoprenyl benzophenone; C414433:guttiferone E