Curcumin is an Inhibitor of p300 Histone Acetylatransferase

Abstract

Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that alpha, beta unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degradation of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addition to inducing p300 degradation curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent association with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compound for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.

Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention

“…Curcumin also has been reported to alter HDAC2 expression by chemically preventing its degradation in human monocytes [67]. The α, β-unsaturated carbonyl groups in the side-chain of curcumin are considered to be structurally important for its HAT inhibitory activity [68]. Curcumin also was found to promote proteasomal degradation of p300 and related HATs in prostate cancer cells and peripheral blood lymphocytes [68].…”

“…The α, β-unsaturated carbonyl groups in the side-chain of curcumin are considered to be structurally important for its HAT inhibitory activity [68]. Curcumin also was found to promote proteasomal degradation of p300 and related HATs in prostate cancer cells and peripheral blood lymphocytes [68]. Recently, curcumin was found to reduce the acetylation of histone H3 in the IL-6 promoter leading to its decreased expression in rheumatoid arthritis synovial fibroblasts [69].…”

Synthesis of Benzamides Related to Anacardic Acid and Their Histone Acetyltransferase (HAT) Inhibitory Activities

“…Inhibitors of HDAC enzymes (HDACis) have shown anticancer potential and already entered the clinic (SAHA, vorinostat, Zolinza have been approved for the treatment of advanced cutaneous T-cell lymphoma, CTCL). [9,18,19] Figure 1 depicts selected HAT modulators of different structural classes including the bi-substrate competitors H3-CoA-201 and construct 2, [20][21][22] simple molecules such as MC1626 4, [23] 5 [24] and MB-3 3 [25] and also the natural products curcumin 6, [26,27] garcinol 9 [28] (and its derivative LTK-14 10 [29] ) and anacardic acid (AA) 7.…”

Chemical Reporter for Visualizing Metabolic Cross-Talk between Carbohydrate Metabolism and Protein Modification

“…13 NIH3T3 cells were treated with or without sodium acetate (10 mM) and 1-deoxy-Ac 3 GlcNAlk (200 μM) for 6 h. In-gel fluorescence showed that sodium acetate was able to compete 1-deoxy-GlcNAlk labeling (Figure 2B). To investigate whether any observed protein acetylation by 1-deoxy-GlcNAlk is enzymatic in nature, NIH3T3 cells were pretreated with curcumin (60 μM) for 30 min prior to treatment with 1-deoxy-Ac 3 GlcNAlk (200 μM) for 5.5 h. Cell lysates were then subjected to CuAAC with az-rho and analyzed by in-gel fluorescence scanning (Figure 2C).…”

“…Likewise, treatment with curcumin resulted in dramatic reduction of the labeling of proteins at low molecular weights but less-so for other proteins. Since curcumin is a specific inhibitor of the p300 acetyltransferase, 13 the proteins that show no change in labeling intensity might be modified by other acetyltransferases. We next directly compared 1-deoxy-GlcNAlk with pentynoic acid.…”