The Protein Acetyltransferase ARD1: A Novel Cancer Drug Target?

Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway.
Current cancer drug targets (Impact Factor: 3.52). 12/2008; 8(7):545-53. DOI: 10.2174/156800908786241113
Source: PubMed


Evasion of apoptosis and active cell proliferation are among the characteristics of cancer cells. Triggering the induction of apoptosis or reducing the proliferative rate will potentially be helpful for cancer treatment. Recently, several reports demonstrated that knockdown of the protein acetyltransferase hARD1 significantly reduced the growth rate of human cancer cell lines. Furthermore, hARD1 knockdown induced apoptosis or sensitized cells to drug induced apoptosis. hARD1 acts in complex with the NATH protein and catalyzes cotranslational acetylation of protein N-termini. Thus, it was suggested that the effects on cell proliferation and apoptosis induction are due to a reduced level of N-terminal acetylation of certain substrate proteins. NATH was originally identified as upregulated in thyroid papillary carcinomas and has lately also been found to correlate with aggressiveness and differentiation status of neuroblastic tumours. On the other hand, researchers recently reported that hARD1 acetylates Beta-catenin. Knockdown of hARD1 reduced the transcriptional activity of the Beta-Catenin/TCF4 complex, downregulating cyclin D1 and thereby promoting G1-arrest and inhibition of cell proliferation of lung cancer cells. Although the underlying molecular mechanisms need further clarification, several reports suggest that reduction of hARD1 negatively affects cell growth. Thus, hARD1 or the hARD1-NATH complex stands out as attractive drug targets in cancer treatment. One challenge will be to develop specific inhibitors that discriminate between hARD1 and the many other enzymes, including the histone acetyltransferases, using acetyl-coenzyme A as acetyl donor. This review focuses on the enzymatic and biological activities of hARD1, and potential mechanisms of functional inhibition.

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    • "Many studies have reported that the overexpression of hArd1 appears to correlate with low survival rate and tumor aggressiveness [13] [15]. It was reported that knockout of human Ard1 significantly reduced the growth rate of human cancer cell lines [17] and was responsible for inducing apoptosis or sensitizing cells to drug-induced apoptosis [8]. As Biochimica et Biophysica Acta 1844 (2014) 1790–1797 Abbreviations: Ard1, arrest defective 1 protein; Ac-CoA, acetyl coenzyme A; CoA, coenzyme A; Alba, acetylation lowers binding affinity; NATs, N-terminal acetyltransferases; HDACs, histone deacetyltransferases ⁎ Corresponding author. "
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    ABSTRACT: Acetylation and deacetylation reactions result in biologically important modifications that are involved in normal cell function and cancer development. These reactions, carried out by protein acetyltransferase enzymes, act by transferring an acetyl group from acetyl-coenzyme A (Ac-CoA) to various substrate proteins. Such protein acetylation remains poorly understood in Archaea, and has been only partially described. Information processing in Archaea has been reported to be similar to that in eukaryotes and distinct from the equivalent bacterial processes. The human N-acetyltransferase Ard1 (hArd1) is one of the acetyltransferases that has been found to be overexpressed in various cancer cells and tissues, and knockout of the hArd1 gene significantly reduces growth rate of the cancer cell lines. In the present study, we determined the crystal structure of Thermoplasma volcanium Ard1 (Tv Ard1), which shows both ligand-free and multiple ligand-bound forms, i.e., Ac-CoA- and coenzyme A (CoA) -bound forms. The difference between ligand-free and ligand-bound chains in the crystal structure was used to search for the interacting residues. The re-orientation and position of the loop between β4 and α3 including the phosphate-binding loop (P-loop) were observed, which are important for the ligand interaction. In addition, a biochemical assay to determine the N-acetyltransferase activity of Tv Ard1 was performed using the Thermoplasma volcanium substrate protein Alba (Tv Alba). Taken together, the findings of this study elucidate ligand-free form of Tv Ard1 for the first time and suggest multiple modes of binding with Ac-CoA and CoA.
    Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 10/2014; 1844(10). DOI:10.1016/j.bbapap.2014.07.011 · 2.75 Impact Factor
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    • "Using novel methods and approaches , it is estimated that in humans (HeLa cells) approximately 85% of the proteins may be N-terminally acetylated [34] [54]. Nαacetylation is a common cotranslational – and a rather rare posttranslational – process catalyzed by the highly conserved N-terminal acetyltransferases , which differ in their specificity towards the N-terminal amino acid [55]. Although N-terminal acetylation is considered irreversible , recent data have shown that some of the proteins are incompletely Nα-acetylated [56]. "
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    ABSTRACT: Voltage-dependent anion channels are abundant mitochondrial outer membrane proteins expressed in three isoforms, VDAC1-3, and are considered as "mitochondrial gatekeepers". Most tissues express all three isoforms. The functions of VDACs are several-fold, ranging from metabolite and energy exchange to apoptosis. Some of these functions depend on or are affected by interaction with other proteins in the cytosol and intermembrane space. Furthermore, the function of VDACs, as well as their interaction with other proteins, is affected by posttranslational modification, mainly phosphorylation. This review summarizes recent findings on posttranslational modification of VDACs and discusses the physiological outcome of these modifications. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.
    Biochimica et Biophysica Acta 11/2011; 1818(6):1520-5. DOI:10.1016/j.bbamem.2011.11.013 · 4.66 Impact Factor
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    • "Furthermore we show that protein N-alphaacetylation is sensitive to acute changes in acetyl-CoA availability. Since incomplete Nalpha-acetylation status of proteins has been described by recent proteome studies (Arnesen et al., 2008; Goetze et al., 2009), we propose that protein N-alpha-acetylation might be a regulated process. In the course of our studies, we noted that protein N-alpha-acetylation levels as assessed by subtiligase were sensitive to nutrient levels in the culture medium (Yi CH and Yuan J, unpublished observations). "
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    ABSTRACT: Previous experiments suggest a connection between the N-alpha-acetylation of proteins and sensitivity of cells to apoptotic signals. Here, we describe a biochemical assay to detect the acetylation status of proteins and demonstrate that protein N-alpha-acetylation is regulated by the availability of acetyl-CoA. Because the antiapoptotic protein Bcl-xL is known to influence mitochondrial metabolism, we reasoned that Bcl-xL may provide a link between protein N-alpha-acetylation and apoptosis. Indeed, Bcl-xL overexpression leads to a reduction in levels of acetyl-CoA and N-alpha-acetylated proteins in the cell. This effect is independent of Bax and Bak, the known binding partners of Bcl-xL. Increasing cellular levels of acetyl-CoA by addition of acetate or citrate restores protein N-alpha-acetylation in Bcl-xL-expressing cells and confers sensitivity to apoptotic stimuli. We propose that acetyl-CoA serves as a signaling molecule that couples apoptotic sensitivity to metabolism by regulating protein N-alpha-acetylation.
    Cell 08/2011; 146(4):607-20. DOI:10.1016/j.cell.2011.06.050 · 32.24 Impact Factor
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