HDACs and HDAC inhibitors in colon cancer

Mariadason, John M.

doi:10.4161/epi.3.1.5736

Cited by 196 publications

(201 citation statements)

References 138 publications

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“…The classical class I, II and IV HDAC inhibitors induce tumour-cell death, with all of the biochemical and morphological characteristics of apoptosis (Mariadason, 2008). The earlier described class III HDAC inhibitors can also induce apoptosis, although the effect depends on the tumour type and stress conditions (Heltweg et al, 2006).…”

Section: Salermide Induces Apoptosis In Cancer But Not In Normal Cellsmentioning

confidence: 99%

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

et al. 2008

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Section: Salermide Induces Apoptosis In Cancer But Not In Normal Cellsmentioning

confidence: 99%

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

et al. 2008

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“…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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“…Suberoylanilide hydroxamic acid and trichostatin A are also involved as HDAC inhibitors. 25,26 As observed with butyric acid, trichostatin A also induced MFG-E8 expression in the colon epithelial cell lines in a time-dependent manner (Figure 3c). These results suggest that the increased expression of MFG-E8 induced by butyric acid is due to hyperacetylation around the promoter region of that growth factor.…”

Section: Butyric Acid Changes Histone Modifications Around Mfg-e8 Promentioning

confidence: 73%

Butyric acid attenuates intestinal inflammation in murine DSS-induced colitis model via milk fat globule-EGF factor 8

Mishiro

Kusunoki

Otani

et al. 2013

Laboratory Investigation

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Butyric acid, a short-chain fatty acid and one of the main metabolites of intestinal microbial fermentation of dietary fiber, has been shown to have an important role in maintaining the integrity of the intestinal mucosa, while it also has been shown to exert potent anti-inflammatory effects both in vitro and in vivo. However, the precise mechanisms underlying those effects have not been fully identified. We exposed colonic epithelial cells to butyric acid, then extracted total RNA samples, and subsequently hybridized them to microarray chips. Among the upregulated genes, milk fat globuleepidermal growth factor 8 (MFG-E8) was elevated by approximately fivefold. We previously reported that the potential therapeutic benefits of MFG-E8 in intestinal tissue injury were dependent not only on enhanced clearance of apoptotic cells but also required diverse cellular events for maintaining epithelial integrity. The influence of butyric acid on cell function is often attributed to its inhibition of histone deacetylases (HDACs). We found that acetylation on histone 3 lysine 9 (acetyl-H3K9) around the MFG-E8 promoter was significantly increased with butyric acid exposure. Experimental colitis was induced by administration of dextran sodium sulfate (DSS) in C57BL/6N (MFG-E8 þ / þ ) and MFG-E8 À / À mice. Although the colonic bacterial compositions in wild-type (WT) and MFG-E8 À / À mice were not significantly different, intrarectal administration of butyric acid during an acute phase of colitis attenuated intestinal inflammatory parameters and inhibited body weight loss in the WT mice. Our novel findings suggest that butyric acid has significant antiinflammatory effects partly via MFG-E8 on DSS-induced murine experimental colitis.

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HDACs and HDAC inhibitors in colon cancer

Cited by 196 publications

References 138 publications

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

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

Butyric acid attenuates intestinal inflammation in murine DSS-induced colitis model via milk fat globule-EGF factor 8

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