Inhibition of Lysine Acetyltransferase KAT3B/p300 Activity by a Naturally Occurring Hydroxynaphthoquinone, Plumbagin

Abstract

Lysine acetyltransferases (KATs), p300 (KAT3B), and its close homologue CREB-binding protein (KAT3A) are probably the most widely studied KATs with well documented roles in various cellular processes. Hence, the dysfunction of p300 may result in the dysregulation of gene expression leading to the manifestation of many disorders. The acetyltransferase activity of p300/CREB-binding protein is therefore considered as a target for new generation therapeutics. We describe here a natural compound, plumbagin (RTK1), isolated from Plumbago rosea root extract, that inhibits histone acetyltransferase activity potently in vivo. Interestingly, RTK1 specifically inhibits the p300-mediated acetylation of p53 but not the acetylation by another acetyltransferase, p300/CREB-binding protein -associated factor, PCAF, in vivo. RTK1 inhibits p300 histone acetyltransferase activity in a noncompetitive manner. Docking studies and site-directed mutagenesis of the p300 histone acetyltransferase domain suggest that a single hydroxyl group of RTK1 makes a hydrogen bond with the lysine 1358 residue of this domain. In agreement with this, we found that indeed the hydroxyl group-substituted plumbagin derivatives lost the acetyltransferase inhibitory activity. This study describes for the first time the chemical entity (hydroxyl group) required for the inhibition of acetyltransferase activity.

Writers and Readers of Histone Acetylation: Structure, Mechanism, and Inhibition

“…5D) (Choi et al 2009), and plumbagin ( Fig. 5E) (Ravindra et al 2009 Some high-throughput screens have been reported, identifying HAT inhibitors with similarly modest potencies to the compounds discussed in the previous paragraph. The high-throughput screening of a 70,000 compound library yielded a family of isothiazolones (CCT077791 and CCT077792) as PCAF inhibitors that were subsequently derivatized as low micromolar PCAF and p300 inhibitors ( Fig.…”

Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines

“…However, the role of curcumin as an acetyltransferase inhibitor has not been investigated in that study. Another example with p300/CBP HAT inhibiting abilities is plumbagin (43), which induces apoptosis and inhibits invasion of prostate cancer cells by several mechanisms including blocking of DNA-binding ability of NF-kB (44). Again, in this context, the role of plumbagin as acetyltransferase inhibitor was not analyzed.…”

Epigenetic changes induced by curcumin and other natural compounds

“…Plumbagin is another agent, derived from Plumbago rosea root extract, that has been found to potently inhibit HAT activity (Ravindra et al 2009). Plumbagin derivatives without a hydroxyl group lost HAT inhibitory activity, indicating that the hydroxyl group is required for this activity.…”