The identification of a novel natural activator of p300 histone acetyltranferase provides new insights into the modulation mechanism of this enzyme.
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.
Dal Piaz
Fabrizio
F
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo 1, 84084 Fisciano, SA, Italy. fdalpiz@unisa.it
Tosco
Alessandra
A
Eletto
Daniela
D
Piccinelli
Anna L
AL
Moltedo
Ornella
O
Franceschelli
Silvia
S
Sbardella
Gianluca
G
Remondelli
Paolo
P
Rastrelli
Luca
L
Vesci
Loredana
L
Pisano
Claudio
C
De Tommasi
Nunziatina
N
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
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