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. 2020 Nov 20;15(11):2866-2871.
doi: 10.1021/acschembio.0c00719. Epub 2020 Oct 9.

Garcinol Is an HDAC11 Inhibitor

Se In Son  1 , Dan Su  1 , Thanh Tu Ho  1 , Hening Lin  1   2
Affiliations

Garcinol Is an HDAC11 Inhibitor

Se In Son et al. ACS Chem Biol. .

Abstract

Garcinol is a natural product from the Garcinia Indica fruit and is well-known as an antioxidant, anti-inflammatory, and anticancer agent. However, the understanding of its mechanism of action is still incomplete. It has been reported to be a histone acetyltransferase (HAT) inhibitor. Here, we surprisingly found that garcinol is a potent histone deacetylase 11 (HDAC11) inhibitor (IC50 ∼ 5 μM in vitro with the HPLC assay and IC50 ∼ 10 μM in the cellular SHMT2 fatty acylation assay), which is comparable to previously reported HDAC11 inhibitors. Additionally, among all the HDACs tested, garcinol specifically inhibits HDAC11 over other HDACs. HDAC11 is the only class IV HDAC, and there are very few inhibitors available for it. Therefore, this study provides a new HDAC11 inhibitor lead from natural products and may help explain the various biological activities of garcinol.

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Figures

Figure 1.
Figure 1.
Structure and biological activities of Garcinol.
Figure 2.
Figure 2.
Garcinol is an HDAC11-specific inhibitor in vitro. (A) Structures of metal-chelating groups-containing natural products tested for HDAC11 inhibition. The percent of inhibition at 10 μM concentration is indicated. (B) HDAC11 inhibition curves of Garcinol on two different myristoyl peptides. (C) Lineweaver-Burk plot for Garcinol. (D) IC50 values of Garcinol on different HDACs. The following substrates were used in the assays: a, myristoyl H3K9; b, acetyl H3K9; c, trifluoroacetyl H3K9; and d, acetyl p53.
Figure 3.
Figure 3.
Garcinol inhibits HDAC11 in cells. (A) Garcinol increases the fatty acylation level of SHMT2, a substrate of HDAC11. (B) Garcinol does not affect the acetylation level of Histone H3, with or without co-incubation with trapoxin A (TpxA) in HEK293T. (C) Garcinol does not significantly affect the acetylation level of Histone H4, with or without co-incubation with trichostatin A (TSA) in HeLa cells. (D) HEK293T cell viability with Garcinol, Isogarcinol and SIS17. Signal intensities (quantified by ImageJ) shown in A-C were normalized to input SHMT2, actin, histone H4 levels, respectively.
Figure 4.
Figure 4.
The enol form of the β-diketone moiety is likely the zinc binding group of Garcinol. (A) Speculation of possible zinc-binding groups in Garcinol. (B) The most probable zinc-binding group of Garcinol based on IC50 of isogarcinol.
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