Emerging Role of Histone Acetyltransferase in Stem Cells and Cancer

Hindawi Stem Cells International Volume 2018, Article ID 8908751, 11 pages https://doi.org/10.1155/2018/8908751 Review Article Emerging Role of Histone Acetyltransferase in Stem Cells and Cancer Daniela Trisciuoglio ,1,2 Marta Di Martile ,2 and Donatella Del Bufalo 1 2 2 Institute of Molecular Biology and Pathology, National Research Council (CNR), Via Degli Apuli 4, Rome 00185, Italy Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy Correspondence should be addressed to Daniela Trisciuoglio; and Donatella Del Bufalo; Received 25 July 2018; Revised 16 October 2018; Accepted 29 October 2018; Published 16 December 2018 Academic Editor: Steven Curley Copyright © 2018 Daniela Trisciuoglio et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Protein acetylation is one of the most important posttranslational modifications catalyzed by acetyltransferases and deacetylases, through the addition and removal of acetyl groups to lysine residues. Lysine acetylation can affect protein-nucleic acid or protein-protein interactions and protein localization, transport, stability, and activity. It regulates the function of a large variety of proteins, including histones, oncoproteins, tumor suppressors, and transcription factors, thus representing a crucial regulator of several biological processes with particular prominent roles in transcription and metabolism. Thus, it is unsurprising that alteration of protein acetylation is involved in human disease, including metabolic disorders and cancers. In this context, different hematological and solid tumors are characterized by deregulation of the protein acetylation pattern as a result of genetic or epigenetic changes. The imbalance between acetylation and deacetylation of histone or nonhistone proteins is also involved in the modulation of the self-renewal and differentiation ability of stem cells, including cancer stem cells. Here, we summarize a combination of in vitro and in vivo studies, undertaken on a set of acetyltransferases, and discuss the physiological and pathological roles of this class of enzymes. We also review the available data on the involvement of acetyltransferases in the regulation of stem cell renewal and differentiation in both normal and cancer cell population. 1. Introduction Epigenetic changes do not involve changes in the DNA sequence but alter the physical structure of DNA. To date, the most commonly epigenetic changes include DNA methylation and histone modifications, such as methylation and acetylation at lysine residues. Lysine acetylation is catalyzed by lysine acetyltransferase, formerly called histone acetyltransferase (HAT), which transfers the acetyl group of acetyl-CoA to the epsilon-amino group of an internal lysine residue located near the amino termini of core histone proteins [1]. The reverse reaction is accomplished by deacetylases (HDAC). More recently, other posttranslational modifications of histones have been described such as neddylation, sumoylation, glycosylation, phosphorylation, poly-ADP ribosylation, and ubiquitination [2]. All these posttranslational modifications of histones, as well as nonhistone proteins, regulate gene expression profiles through their effect on chromatin structure/remodelling. Histone acetylation is associated with an open and active chromatin conformation (i.e., euchromatin), while histone deacetylation is generally associated with a condensed and inactive form of chromatin (i.e., heterochromatin). On the other hand, histone methylation might be a marker for both active chromatin and inactive chromatin. For definition, it is not possible to pass down epigenetic changes to future generations; nevertheless, it is now accepted that epigenetic modifications can cross the border of generations and can be inherited from parent to offspring. In line with the relevance of epigenetic changes in normal development, the first stage of development is evidenced by erasure of epigenetic information compatible for development. This 2 epigenetic phenomenon, named epigenetic reprogramming, is likely required for resetting the epigenome of the early embryo, so that it can form every kind of cell type in the organism. To pass to the next generation, epigenetic information must avoid being erased during reprogramming. Indeed, it is now well accepted that there are rare regulatory elements that evade, for instance, DNA demethylation during embryogenesis, thus suggesting that change in the epigenome can be inherited also transgenerationally [3–5]. In line with this evidence, two recent studies evidence that also maternal inheritance of histone marks trimethylated lysine 27 of histone 3, a repressing mark of gene expression, may represent a conserved mechanism able to regulate gene expression during early development [6, 7]. Overall, these studies recognize the importance of epigenetic programming in determining cell identity during the reprogramming process, indicating that epigenetic information might play a critical role in the restoration of totipotency in the embryo or in stem cells. An aberrant epigenetic signature can be responsible for some disease states causing abnormal activation or silencing of genes playing a role in different pathologies, such as syndromes involving chromosomal instabilities or mental retardation [8, 9]. Epigenetic alterations can also be responsible for the promotion or inhibition of a malignant phenotype at various stages of the disease: in transformed cells, epigenetic changes occur in key oncogenes or tumor suppressor genes leading to cancer initiation or progression [10, 11]. The aim of this review is to discuss the role of protein acetylation leading to cancer initiation and progression, and their role in the maintenance of stem cell progenies and how deregulation of HAT in this subpopulation sustains tumor development. 2. HAT: Classification and Functions Histone acetylation is preferentially carried out on specific lysine: for instance, histone H3 is mainly acetylated in positions 9, 14, 18, and 23, while the lysine of histone H4 that are preferentially acetylated are in positions 5, 8, 12, and 16. The addition of the acetyl group neutralizes the positive charge of lysine weakening the electrostatic interaction between the histones and DNA, relaxing the chromatin structure and recruiting chromatin remodelling protein complexes (e.g., transcription factors and chromatin modifiers), and finally leading to gene activation. Recent analysis of lysine acetylation through mass spectrometry has increased our understanding on this posttranslational modification [12] and demonstrated the involvement of HAT enzymes in many biological processes beyond gene transcription, through the regulation of protein interaction, (...truncated)