Dietary Compound Resveratrol Is a Pan-BET Bromodomain Inhibitor

Abstract

The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2.0 °C. The micromolar dissociation constant (Kd) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV Kd value accounted to 6.6 µM in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.

Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin

“…Bromodomains are acetylated‐lysines (Kac) recognizing modules, generally associated with additional domains involved in chromatin remodelling and transcriptional regulation ; bromodomains have crucial epigenetic implications in cancer, inflammation and neurological disorders, with a number of inhibitors in clinical trials . Various compounds, which share a similar chemical organization with curcumin degradation products, were recently reported as micromolar inhibitors of BET (bromodomain and extra‐terminal motif proteins: BRD2, BRD3, BRD4 and BRDT) bromodomains . Ferulic acid is shown here to bind in the Kac pocket of the first BRD4 bromodomain.…”

“…Owing to the similarity of ferulic acid with previously reported BET bromodomains inhibitors , the compound was soaked into apo crystals of the BRD4 first bromodomain. The guaiacol group binds in the deepest part of the pocket with the hydroxyl group recapitulating the interactions of the acetyl group of Kac with the protein matrix; two hydrogen bonds are formed between the guaiacol hydroxyl and the evolutionary conserved Asn140 and Tyr97 (water‐bridged for this last, Fig.…”

Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers

“…Resveratrol is anti-methylation and pro-acetylation, given its capability to inhibit DNMT1, DNMT3A, DNMT3B, HDAC1, and MeCP2 [ 31 ]. Computational predictions have shown that resveratrol might also have significant interactions with epigenetic readers such as BRD4 bromodomain 1, which reads acetylated histone lysine residues and plays significant roles in cell proliferation repression in cancer [ 32 , 33 ]. Recent studies have emphasized a resveratrol-derivative referred to as pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene; Figure 1 e), which has a higher bioavailability and potency compared with resveratrol for inhibiting the growth of cancer cells and cancer stem cells in cervical cancer [ 34 ].…”

Targeting Epigenetic ‘Readers’ with Natural Compounds for Cancer Interception

“…In particular, resveratrol induces both intrinsic and extrinsic apoptotic pathways and interferes with different stages of cancer development [ 111 ]. Recent reports indicated that resveratrol might act as a pan-BET inhibitor [ 112 ]. Using isothermal titration calorimetry, a dissociation constant (K d ) of 6.6 µM towards BRD4(1) was found, corroborated by molecular docking studies in silico that showed favorable acetyl-lysine binding site interactions of resveratrol.…”