Metabolism as a key to histone deacetylase inhibition

Rajendran, Praveen; Williams, David E.; Ho, Emily; Dashwood, Roderick H.

doi:10.3109/10409238.2011.557713

Cited by 68 publications

(68 citation statements)

References 221 publications

(275 reference statements)

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“…Metabolism of the major dietary forms of selenium methylselenocysteine and selenomethionine can generate ␤ -methylselenopyruvate and ␣ -keto-␥ -methylselenobutyrate, respectively, that comprise seleno-␣ -keto acids that have been identified as novel HDACi [111] . These organoselenium metabolites induced H3 hyperacetylation (10 and 50 M for both compounds) in different prostate cancer cells (LNCaP, LNCaPC4-2 and PC3) and inhibited HDAC activity in nuclear fractions of these cells (0.025-2.5 m M for ␤ -methylselenopyruvate and 0.25-2.5 m M for ␣ -keto-␥ -methylselenobutyrate) [112] .…”

Section: Seleniummentioning

confidence: 99%

Targeting the Epigenome with Bioactive Food Components for Cancer Prevention

2011

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Epigenetic processes participate in cancer development and likely influence cancer prevention. Global DNA hypomethylation, gene promoter hypermethylation and aberrant histone posttranslational modifications are hallmarks of neoplastic cells which have been associated with genomic instability and altered gene expression. Because epigenetic deregulation occurs early in carcinogenesis and is potentially reversible, intervention strategies targeting the epigenome have been proposed for cancer prevention. Bioactive food components (BFCs) with anticancer potential, including folate, polyphenols, selenium, retinoids, fatty acids, isothiocyanates and allyl compounds, influence DNA methylation and histone modification processes. Such activities have been shown to affect the expression of genes involved in cell proliferation, death and differentiation that are frequently altered in cancer. Although the epigenome represents a promising target for cancer prevention with BFCs, few studies have addressed the influence of dietary components on these mechanisms in vivo, particularly on the phenotype of humans, and thus the exact mechanisms whereby diet mediates an effect on cancer prevention remains unclear. Primary factors that should be elucidated include the effective doses and dose timing of BFCs to attain epigenetic effects. Because diet-epigenome interactions are likely to occur in utero, the impact of early-life nutrition on cancer risk programming should be further investigated.

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Section: Seleniummentioning

confidence: 99%

Targeting the Epigenome with Bioactive Food Components for Cancer Prevention

2011

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“…Of particular interest is the elucidation of the polypharmacological behavior of dietary and nutraceutical components. Indeed, many clinical, physiopathological and epidemiological studies highlighted the detrimental or beneficial role of nutritional factors in conjunction to epigenetic alterations [27,37,66,91,238,593].…”

Section: Understanding the Selectivity/polypharmacologymentioning

confidence: 99%

“…Deacetylation of histones alters the chromatin structure and represses transcription. Abnormal activity of these enzymes is implicated in several diseases, especially in cancer [20,23,31,98,107,136,159,[232][233][234][235][236][237][238].…”

Section: Class I Ii and Iv Deacetylasesmentioning

confidence: 99%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

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“…Royal jelly and butyrate are both used as dietary supplements in humans, and their long-term use may have epigenetic effects as a consequence. Indeed, cruciferous vegetables and green tea extracts also contain chemicals with histone deacetylase inhibitory activity (81). Finally, heavy metals such as arsenic and cadmium also affect epigenetic regulation, possibly through histone methylation (17).…”

Section: Figurementioning

confidence: 99%

Diet, Nutrition, and Cancer Epigenetics

2016

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The search for a connection between diet and human cancer has a long history in cancer research, as has interest in the mechanisms by which dietary factors might increase or decrease cancer risk. The realization that altering diet can alter the epigenetic state of genes and that these epigenetic alterations might increase or decrease cancer risk is a more modern notion, driven largely by studies in animal models. The connections between diet and epigenetic alterations, on the one hand, and between epigenetic alterations and cancer, on the other, are supported by both observational studies in humans as well as animal models. However, the conclusion that diet is linked directly to epigenetic alterations and that these epigenetic alterations directly increase or decrease the risk of human cancer is much less certain. We suggest that true and measurable effects of diet or dietary supplements on epigenotype and cancer risk are most likely to be observed in longitudinal studies and at the extremes of the intersection of dietary risk factors and human population variability. Careful analysis of such outlier populations is most likely to shed light on the molecular mechanisms by which suspected environmental risk factors drive the process of carcinogenesis.

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Metabolism as a key to histone deacetylase inhibition

Cited by 68 publications

References 221 publications

Targeting the Epigenome with Bioactive Food Components for Cancer Prevention

Targeting the Epigenome with Bioactive Food Components for Cancer Prevention

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Diet, Nutrition, and Cancer Epigenetics

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