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: 4.05). 10/2008; 41(1):185-98. DOI: 10.1016/j.biocel.2008.08.027
Source: PubMed


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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Available from: Tobias Wagner, Jul 30, 2014
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    • "Histone deacetylase (HDAC) activities are essential for the removal of acetyl groups from the e-amino group of lysine residues leading to modulation of activity, cellular localization or stability of targeted proteins [1] [2] [3]. The HDAC family contains eighteen members divided in four classes: class I (HDAC1, 2, 3, 8), class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10), class III (sirtuins 1–7) and class IV (HDAC11). "
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    ABSTRACT: Histone deacetylase (HDAC)6 is a unique isoenzyme targeting specific substrates including α-tubulin and heat shock protein (HSP)90. HDAC6 is involved in protein trafficking and degradation, cell shape and migration. Deregulation of HDAC6 activity is associated with a variety of diseases including cancer leading to a growing interest for developing HDAC6 inhibitors. Here, we identified two new structurally related 4-hydroxybenzoic acids as selective HDAC6 inhibitors reducing proliferation, colony and spheroid formation as well as viability of prostate cancer cells. Both compounds strongly enhanced α-tubulin acetylation leading to remodeling of microtubular organization. Furthermore, 4-hydroxybenzoic acids decreased HSP90α regulation of the human androgen receptor in prostate cancer cells by increasing HSP90α acetylation levels. Collectively, our data support the potential of 4-hydroxybenzoic acid derivatives as HDAC6-specific inhibitors with anti-cancer properties.
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    • "HDACs together with histone lysine acetyltransferases (HATs) are responsible for the balance between acetylated/deacetylated states of histones, therefore transform the chromatin structure and alter gene transcription. Growing number of identified acetylated non-histone proteins demonstrate that reversible lysine acetylation also influence mRNA stability, and the localisation, interaction, degradation and function of non-histone proteins (Choudhary et al., 2009; Spange et al., 2009). HDAC inhibitors (HDACi) generally lead to growth arrest, differentiation and apoptosis of malignant cells, and have been extensively explored as potential anti-cancer agents (West & Johnstone, 2014). "
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    • "Since the acetylation status of histones is critical for the gene expression modulation and cell fate, there is no surprise that its dysregulation is involved in the development of several cancers. Recent studies revealed that HDACs are responsible for the deacetylation of several nonhistones too, such as proteins relevant for tumorigenesis, for cancer cell proliferation, and for immune functions [11] [12]. "
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    ABSTRACT: In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.
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