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Acetylation of non-histone proteins modulates cellular signalling at multiple levels

Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
The International Journal of Biochemistry & Cell Biology (Impact Factor: 4.24). 10/2008; 41(1):185-98. DOI: 10.1016/j.biocel.2008.08.027
Source: PubMed

ABSTRACT This review focuses on the posttranslational acetylation of non-histone proteins, which determines vital regulatory processes. The recruitment of histone acetyltransferases and histone deacetylases to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation and differentiation. A steadily growing number of identified acetylated non-histone proteins demonstrate that reversible lysine acetylation affects mRNA stability, and the localisation, interaction, degradation and function of proteins. Interestingly, most non-histone proteins targeted by acetylation are relevant for tumourigenesis, cancer cell proliferation and immune functions. Therefore inhibitors of histone deacetylases are considered as candidate drugs for cancer therapy. Histone deacetylase inhibitors alter histone acetylation and chromatin structure, which modulates gene expression, as well as promoting the acetylation of non-histone proteins. Here, we summarise the complex effects of dynamic alterations in the cellular acetylome on physiologically relevant pathways.

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    • "The enzyme family of HDAC contributes to post-translational protein modifications by catalysing the deacetylation of lysine residues in their target proteins [7] [8]. These include not only DNA-associated histones but also a great number of non-histone proteins such as transcription factors and regulators, signal transduction mediators, as well as chaperone and structural proteins [9] [10] [11]. HDAC belonging to class I (HDAC1, 2, 3 and 8), class IIa (HDAC4, 5, 7, 9), and class IIb (HDAC6 and 10) [2] [12] share a zinc(II) cation in the centre of their catalytic cavity, yet differ in their cellular function, (tissue) localisation and protein substrates [2] [10]. "
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    ABSTRACT: Histone deacetylases (HDAC) which play a crucial role in cancer cell proliferation are promising drug targets. However, HDAC inhibitors (HDACi) modelled on natural hydroxamic acids such as trichostatin A frequently lead to resistance or even an increased agressiveness of tumours. As a workaround we developed 4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide (etacrox), a hydroxamic acid that combines HDAC inhibition with synergistic effects of the 4,5-diarylimidazole residue. Etacrox proved highly cytotoxic against a panel of metastatic and resistant cancer cell lines while showing greater specificity for cancer over non-malignant cells when compared to the approved HDACi vorinostat. Like the latter, etacrox and the closely related imidazoles bimacroxam and animacroxam acted as pan-HDACi yet showed some specificity for HDAC6. Akt signalling and interference with nuclear beta-catenin localisation were elicited by etacrox at lower concentrations when compared to vorinostat. Moreover, etacrox disrupted the microtubule and focal adhesion dynamics of cancer cells and inhibited the proteolytic activity of prometastatic and proangiogenic matrix metalloproteinases. As a consequence, etacrox acted strongly antimigratory and antiinvasive against various cancer cell lines in three-dimensional transwell invasion assays and also antiangiogenic in vivo with respect to blood vessel formation in the chorioallantoic membrane assay. These pleiotropic effects and its water-solubility and tolerance by mice render etacrox a promising new HDACi candidate. Copyright © 2015. Published by Elsevier Inc.
    Experimental Cell Research 06/2015; 336(2):263-275. DOI:10.1016/j.yexcr.2015.06.008 · 3.37 Impact Factor
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    • "Acetilación de proteínas no histonas muy próximos, se ha sugerido que puede existir algún tipo de cooperación o interferencia entre estas dos vías de transmisión de señales (Kouzarides, 2000; Spange y col, 2009). "
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    Sociedad Española de Ciencias Fisiológicas (ISSN: 1889-397X), Spain; 12/2014
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    • "However, the present study did not demonstrate the exact mechanism by which NaB displays an effective reduction of excessive alcohol intake in dependent animals. It is noteworthy that other mechanisms such as acetylation of non-histone targets cannot be ruled out (Spange et al. 2009). It is interesting to note that when NaB and MS-275 were no longer administered, D rats quickly recovered their excessive ethanol self-administration, except at the "
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    ABSTRACT: Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.
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