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Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells cancers Review Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells Anna Wawruszak 1,* , Joanna Kalafut 1, Estera Okon 1, Jakub Czapinski 1,2, Marta Halasa 1, Alicja Przybyszewska 1, Paulina Miziak 1, Karolina Okla 3,4, Adolfo Rivero-Muller 1,5,† and Andrzej Stepulak 1,† 1 Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland; [email protected] (J.K.); [email protected] (E.O.); [email protected] (J.C.); [email protected] (M.H.); [email protected] (A.P.); [email protected] (P.M.); [email protected] (A.R.-M.); [email protected] (A.S.) 2 Postgraduate School of Molecular Medicine, Medical University of Warsaw, Trojdena 2a St., 02-091 Warsaw, Poland 3 The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland; [email protected] 4 Tumor Immunology Laboratory, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland 5 Faculty of Science and Engineering, Cell Biology, Abo Akademi University, Tykistokatu 6A, 20520 Turku, Finland * Correspondence: [email protected]; Tel.: +48-81-448-6350 † These authors contributed equally to this work. Received: 23 December 2018; Accepted: 22 January 2019; Published: 27 January 2019 Abstract: Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT. Keywords: cancer; HDI; HDAC; EMT; MET; cadherin; catenin; vimentin; migration; invasion 1. Introduction Epithelial-mesenchymal transition (EMT) is a biological reversible process in which cells undergo multiple biochemical changes—lose their epithelial properties, including cell-cell adhesion and cell polarity, and acquire mesenchymal phenotype, including the ability to invade the extracellular matrix (ECM) and potentially migrate to the distant places. Induction of EMT includes reorganization of cytoskeleton proteins, activation of transcription factors and production of extracellular matrix-degrading enzymes [1,2]. Recent studies revealed the large role of epigenetic mechanisms including DNA methylation, chromatin rearrangement, histone modifications and non-coding RNAs in the initiation and progression of cancers [3]. Histone modifications play important Cancers 2019, 11, 148; doi:10.3390/cancers11020148 www.mdpi.com/journal/cancers Cancers 2019, 11, 148 2 of 31 Cancers 2019, 11, x 2 of 31 rolesmodulators, in gene expressionwhich also regulationcontrols phenotypic via changes transf in chromaticormation. structureAbnormal and histon recruitmente modification of epigenetic patterns modulators,are closely associated which also with controls numerous phenotypic diseases transformation. including cancers, Abnormal thus they histone are modificationconsidered promising patterns arebiomarkers closely associated [4]. with numerous diseases including cancers, thus they are considered promising biomarkersHistone [4 ].deacetylase inhibitors (HDIs) are effective anti-cancer agents which, in monotherapy and/orHistone in combination deacetylase inhibitorswith conventional (HDIs) are chemot effectiveherapeutics, anti-cancer exhibit agents anti-neoplastic which, in monotherapy properties and/orthrough in cell-cycle combination arrest, with inhibition conventional of migration chemotherapeutics, and invasion, exhibit induction anti-neoplastic of differentiation properties and throughapoptosis cell-cycle in many arrest, types inhibition of cancer of migration cells [5–8]. and invasion,Combinations induction of ofHDIs differentiation with e.g., andthienotriazolodiazepine apoptosis in many (JQ1), types an inhibitor of cancer of cellsbromodomain-containing [5–8]. Combinations acetylation of HDIs reader with proteins e.g., thienotriazolodiazepinelike bromodomain-containing (JQ1), an prot inhibitorein 4 of(BRD4), bromodomain-containing have shown efficacy acetylation in several reader cancer proteins types, likeincluding bromodomain-containing urothelial carcinoma protein [9]. It 4 has (BRD4), been havereported shown that efficacy HDIs can in several reverse cancer EMT, types, a process including called urothelialmesenchymal-epithelial carcinoma [9]. transition It has been(MET), reported through, that inter HDIs alia, unblocking can reverse of EMT, E-cadherin a process repression called in mesenchymal-epithelialsolid cancers [10]. Thus, transitionsuggesting (MET), that HDIs through, have a inter therapeutic alia, unblocking role in inhibition of E-cadherin of EMTrepression in cancer incells solid [11–14]. cancers However, [10]. Thus, conflicting suggesting results that HDIshave been have also a therapeutic found, where role inHDIs inhibition induced of EMTEMT inby cancerreversing cells stem [11– 14cell-like]. However, properties conflicting and enhanced results have meta beenstasis also [15]. found, In this where review HDIs we discuss induced the EMT impact by reversingof various stem HDIs cell-like on epithelial properties and and mesenchymal enhanced metastasis markers, [ 15as]. well In this as reviewon migration we discuss and theinvasion impact of ofcancer various cells HDIs (Figure on 1). epithelial The efficacy and mesenchymalof HDIs has been markers, demonstrated as well in as both on migration in vitro and and animal invasion models of cancerin monotherapy cells (Figure and/or1). The in efficacy combination of HDIs with has existing been demonstrated or novel chemotherapeutics. in both in vitro and animal models in monotherapy and/or in combination with existing or novel chemotherapeutics. FigureFigure 1.1. HistoneHistone deacetylasedeacetylase inhibitorsinhibitors (HDIs)(HDIs) modulatemodulate expressionexpression ofof epithelial-mesenchymal epithelial-mesenchymal transitiontransition (EMT) (EMT) markers markersas as well well as as stimulatestimulate oror inhibitinhibit migrationmigration andand invasioninvasion ofof cancercancer cells.cells. ((AA).) HDIsHDIs induce induce EMT EMT by increasingby increasing migration migration and invasion and in ofvasion cancer cellsof cancer by upregulation cells by ofupregulation mesenchymal of markersmesenchymal (N-cadherin, markers vimentin) (N-cadhe andrin, EMT-relatedvimentin) and transcription EMT-related factors transcription (SNAIL ,factorsSLUG ,(SNAIL,TWIST, SLUG,ZEB). (BTWIST,) HDIs upregulateZEB). (B.) expressionHDIs upregulate of epithelial expression markers of (E-cadherin,epithelial markersβ-catenin) (E-cadherin, and consequently β-catenin) inhibit and EMT,consequently migration inhibit and invasion EMT, migration of cancer and cells. invasion of cancer cells. 2. Histone Deacetylases (HDACs) and Histone Deacetylase Inhibitors (HDIs) 2. Histone Deacetylases (HDACs) and Histone Deacetylase Inhibitors (HDIs) Epigenetic regulation of gene expression is largely modulated throughout chromatin and Epigenetic regulation of gene expression is largely modulated throughout chromatin and nucleosome remodeling, which involves histone post-translational modifications (PTMs) [16]. These nucleosome remodeling, which involves histone post-translational modifications (PTMs) [16]. These PTMs result in dynamic shifts between transcriptionally active and suppressed states of chromatin [17]. PTMs result in dynamic shifts between transcriptionally active and suppressed states of chromatin Histone PTMs include methylation, phosphorylation, acetylation, sumoylation, ubiquitination and [17]. Histone PTMs include methylation, phosphorylation, acetylation, sumoylation, ubiquitination ADP-ribosylation [18]. Histone acetylation, one of the most extensively studied PTMs of histones, and ADP-ribosylation [18]. Histone acetylation, one of the most extensively studied PTMs of histones, is regulated by the balance between histone deacetylases (HDACs) and histone acetyltransferases is regulated by the balance between histone deacetylases (HDACs) and histone acetyltransferases (HATs) (Figure2A) [ 16]. HATs are enzymes that transfer an acetyl group from acetyl-CoA to "-amino (HATs) (Figure 2A) [16]. HATs are enzymes that transfer an acetyl group from acetyl-CoA to ε-amino lysine residues located on N-terminus of histones [19]. In contrast, HDACs are responsible for lysine residues located on N-terminus of histones [19]. In contrast, HDACs are responsible for removing the acetyl group from the acetylated lysine residues. This reversible reaction is crucial for removing the acetyl group from the acetylated lysine residues. This reversible reaction is crucial for chromatin structure stabilization and transcriptional
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