Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases

Berger, Alexander; Venturelli, Sascha; Kallnischkies, M; Böcker, Alexander; Busch, Christian; Weiland, Timo; Noor, Seema; Leischner, Christian; Weiss, Thomas S.; Lauer, Ulrich M.; Bischoff, Stephan C.; Bitzer, Michael

doi:10.1016/j.jnutbio.2012.07.001

Cited by 101 publications

(58 citation statements)

References 38 publications

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“…For comparison of the docking results, the scoring function GoldScore was used. Interestingly, 6-PN and 8-PN yielded higher GoldScores than previously published scores for TSA or SAHA [27] for HDAC4 (6-PN: 66.5; 8-PN: 57.6), HDAC7 (6-PN: 56.9; 8-PN: 56.7) and HDAC8 (6-PN: 59.5; 8-PN: 64.8), and GoldScores comparable to (6-PN) or lower (8-PN) than TSA or SAHA for HDAC2 (6-PN: 62.8; 8-PN: 37), with the restriction mentioned above. Taken together, based on the in silico data both 6-PN and 8-PN were suggested to exhibit inhibitory activity against HDAC enzymes of class I and II comparable to standard HDACi such as TSA and SAHA.…”

Section: In Silico Docking Analyses Predicted Binding Of 6-pn and 8-pmentioning

confidence: 46%

6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

Venturelli

Niessner

Sinnberg

et al. 2018

Cell Physiol Biochem

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Background/Aims: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). Methods: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. Results: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. Conclusion: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.

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Section: In Silico Docking Analyses Predicted Binding Of 6-pn and 8-pmentioning

confidence: 46%

6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

Venturelli

Niessner

Sinnberg

et al. 2018

Cell Physiol Biochem

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“…The effects of Kae on regulating histone deacetylases and non-coding RNAs have been reported [27, 28], which may be closely associated with bladder cancer progression [29, 30]. DNA methylation, as a common epigenetic modification, regulates the expression of genes.…”

Section: Discussionmentioning

confidence: 99%

Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

Qiu

Lin

Zhu

et al. 2017

Cell Physiol Biochem

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Background: Genomic DNA methylation plays an important role in both the occurrence and development of bladder cancer. Kaempferol (Kae), a natural flavonoid that is present in many fruits and vegetables, exhibits potent anti-cancer effects in bladder cancer. Similar to other flavonoids, Kae possesses a flavan nucleus in its structure. This structure was reported to inhibit DNA methylation by suppressing DNA methyltransferases (DNMTs). However, whether Kae can inhibit DNA methylation remains unclear. Methods: Nude mice bearing bladder cancer were treated with Kae for 31 days. The genomic DNA was extracted from xenografts and the methylation changes was determined using an Illumina Infinium HumanMethylation 450 BeadChip Array. The ubiquitination was detected using immuno-precipitation assay. Results: Our data indicated that Kae modulated DNA methylation in bladder cancer, inducing 103 differential DNA methylation positions (dDMPs) associated with genes (50 hyper-methylated and 53 hypo-methylated). DNA methylation is mostly relied on the levels of DNMTs. We observed that Kae specifically inhibited the protein levels of DNMT3B without altering the expression of DNMT1 or DNMT3A. However, Kae did not downregulate the transcription of DNMT3B. Interestingly, we observed that Kae induced a premature degradation of DNMT3B by inhibiting protein synthesis with cycloheximide (CHX). By blocking proteasome with MG132, we observed that Kae induced an increased ubiquitination of DNMT3B. These results suggested that Kae could induce the degradation of DNMT3B through ubiquitin-proteasome pathway. Conclusion: Our data indicated that Kae is a novel DNMT3B inhibitor, which may promote the degradation of DNMT3B in bladder cancer.

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“…Furthermore, kaempferol mediated prominent reductions in cell viability and proliferation rate. 67 These findings provided a novel insight to treating colon cancer by inhibition of HDACs.…”

Section: Hdacs and Colon Cancermentioning

confidence: 94%

Histone Deacetylases and Mechanisms of Regulation of Gene Expression

2015

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In recent years, it has become widely recognized that histone modification plays a pivotal role in controlling gene expression, and is involved in a wide spectrum of disease regulation. Histone acetylation is a major modification that affects gene transcription and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDAC). HATs acetylate lysines of histone proteins, resulting in relaxation of chromatin structure, and they also facilitate gene activation. Conversely, HDACs remove acetyl groups from hyperacetylated histones and suppress general gene transcription. In addition to histones, numerous non-histone proteins can be acetylated and deacetylated, and they are also involved in a wide range of disease regulation. To date, there are 18 HDACs in mammals classified into four classes based on homology to yeast HDACs. Accumulating evidence has revealed that HDACs play crucial roles in a variety of biological processes including inflammation, cell proliferation, apoptosis, and carcinogenesis. In this review, we summarize the current state of knowledge of HDACs in carcinogenesis and describe the involvement of HDACs in cancer-associated molecular processes. It is hoped than our understanding of the role of HDACs in cancer will lead to the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease.

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Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases

Cited by 101 publications

References 38 publications

6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

Histone Deacetylases and Mechanisms of Regulation of Gene Expression

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