cancers Review Epigenetic Regulation of TRAIL Signaling: Implication for Cancer Therapy Mohammed I. Y. Elmallah 1,2,* and Olivier Micheau 1,* 1 INSERM, Université Bourgogne Franche-Comté, LNC UMR1231, F-21079 Dijon, France 2 Chemistry Department, Faculty of Science, Helwan University, Ain Helwan 11795 Cairo, Egypt * Correspondence: [email protected] (M.I.Y.E.); [email protected] (O.M.) Received: 23 May 2019; Accepted: 18 June 2019; Published: 19 June 2019 Abstract: One of the main characteristics of carcinogenesis relies on genetic alterations in DNA and epigenetic changes in histone and non-histone proteins. At the chromatin level, gene expression is tightly controlled by DNA methyl transferases, histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyl-binding proteins. In particular, the expression level and function of several tumor suppressor genes, or oncogenes such as c-Myc, p53 or TRAIL, have been found to be regulated by acetylation. For example, HATs are a group of enzymes, which are responsible for the acetylation of histone proteins, resulting in chromatin relaxation and transcriptional activation, whereas HDACs by deacetylating histones lead to chromatin compaction and the subsequent transcriptional repression of tumor suppressor genes. Direct acetylation of suppressor genes or oncogenes can affect their stability or function. Histone deacetylase inhibitors (HDACi) have thus been developed as a promising therapeutic target in oncology. While these inhibitors display anticancer properties in preclinical models, and despite the fact that some of them have been approved by the FDA, HDACi still have limited therapeutic efficacy in clinical terms. Nonetheless, combined with a wide range of structurally and functionally diverse chemical compounds or immune therapies, HDACi have been reported to work in synergy to induce tumor regression. In this review, the role of HDACs in cancer etiology and recent advances in the development of HDACi will be presented and put into perspective as potential drugs synergizing with TRAIL’s pro-apoptotic potential. Keywords: histone deacetylase (HDAC); histone deacetylase inhibitors (HDACIs); chromatin remodeling; cancer; tumor necrosis factor (TNF); TRAIL; methylation; silencing 1. Introduction Cancer is considered as the leading cause of death worldwide. It has been reported to occur as a result of epigenetic modifications, including amplifications, translocations, deletions, and point mutations [1,2]. These epigenetic modifications are linked to abnormal cellular transformation, characterized, among other things, by uncontrolled proliferation and resistance to cell death, forming a lump or what is called a tumor. In addition, DNA methylation and the post-translational modification of proteins such as histones, including acetylation and methylation, are also believed to play a central role in tumorigenesis by modifying the structure of chromatin and the subsequent negative regulation of tumor suppressor genes or oncogenes without any change in the DNA sequence [3]. The main function of histones is the packaging of genomic DNA inside the nucleus. Histone proteins are rich with positively charged amino acids, lysine and arginine, which makes their overall structure positive. In this context, histones can interact with the negatively charged phosphate group of DNA. These proteins are composed of several types of histone including H1, H2A, H2B, H3, and H4. H2A, H2B, H3, and H4 represent the main histone core, while H1 is known as a linker histone [4]. The core multimeric protein is an octamer molecule, mainly consisting of two copies of each histone type (2H2A, 2H2B, 2H3, Cancers 2019, 11, 850; doi:10.3390/cancers11060850 www.mdpi.com/journal/cancers Cancers 2019, 11, x 2 of 31 Cancers 2019, 11, 850 2 of 29 [4]. The core multimeric protein is an octamer molecule, mainly consisting of two copies of each histone type (2H2A, 2H2B, 2H3, and 2H4) forming a globular structure called the nucleosome (Figure and1a). 2H4) Each forming nucleosome a globular is wrapped structure by approx. called the 146 nucleosome bp of DNA and (Figure separated1a). Each by 50 nucleosome base pair (bp) is wrapped linker byDNA. approx. The 146 N-terminal bp of DNA domain and separated of histones by 50 possesses base pair (bp)an unstructured linker DNA. part The N-terminalthat has also domain been of histonessuggested possesses to be involved an unstructured in the epigenetic part that hasmodifi alsocation been of suggested chromatin. to Considering be involved inthe the process epigenetic by modificationwhich histone of chromatin. proteins are Considering post-translationally the process modified, by which histonechromatin proteins adopts are various post-translationally structural modified,conformations chromatin that regulate adopts various both the structural repression conformations and activation thatof gene regulate transcription both the (Figure repression 1b and and activation[5]). of gene transcription (Figure1b and [5]). FigureFigure 1. 1.Illustration Illustration of of histone histone core core composition composition and and impact impact of of chromatin chromatin relaxation relaxation or or compaction compaction by histoneby histone acetyltransferases acetyltransferases (HAT) (HAT) or histone or histon deacetylasese deacetylases (HDAC) (HDAC) on gene on expressiongene expression (a) Histone (a) Histone protein consistsprotein of consists five main of five types main H1, types H2A, H1, H2B, H2A, H3, H2B, and H3, H4. and Two H4. copies Two copies of each of histoneeach histone type type (2H2A, (2H2A, 2H2B, 2H3,2H2B, and 2H3, 2H4) and constitute 2H4) constitute the octamer the octamer histone corehistone (nucleosome), core (nucleosome), wrapped wrapped by approx. by approx. 146 bp 146 of DNA.bp H1of is DNA. known H1 as is linker known histone as linker that ishistone associated that is to associated linker DNA to betweenlinker DNA each between nucleosome. each nucleosome. (b) Epigenetic modification(b) Epigenetic of histone modification proteins of by histone HDAC /proteinsHAT. HAT by stimulatesHDAC/HAT. transcriptional HAT stimulates activation transcriptional of the tumor suppressoractivation genes of the via tumor acetylation suppressor of N-genes"-lysine via acetylation residues of of histone N-ε-lysine results residues in more of histone relaxed results chromatin, in whichmore facilitates relaxed chromatin, the accessibility which offacilitates target gene the promoteraccessibility to of transcription target gene factors.promoter Conversely, to transcription HDAC inducesfactors. transcriptional Conversely, repressionHDAC induces of tumor transcriptio suppressornal genesrepression by deacetylating of tumor suppressor N-"-lysine genes residues by of histonedeacetylating in which N- theε-lysine chromatin residues adopts of compactedhistone in which structure the conformation,chromatin adopts thus compacted hiding the targetstructure gene promoterconformation, from the thus transcription hiding the target factors. gene promoter from the transcription factors. AcetylationAcetylation/deacetylation/deacetylation ofof thethe N-N-"ε-lysine-lysine residues of of histones histones is is regulated regulated by by a agroup group of of acetylatingacetylating and and deacetylating deacetylating enzymes. enzymes. HistoneHistone acet acetyltransferasesyltransferases (HATs) (HATs) transfer transfer an an acetyl acetyl group group fromfrom an an acetyl-coA acetyl-coA molecule molecule toto the N- N-ε"-lysine-lysine residues residues of of histone, histone, resulting resulting in the in theneutralization neutralization of its positive charge and in the activation of gene transcription. In contrast, histone deacetylases of its positive charge and in the activation of gene transcription. In contrast, histone deacetylases (HDACs) remove the acetyl group from the N-ε-lysine residues of histone providing a tight (HDACs) remove the acetyl group from the N-"-lysine residues of histone providing a tight interaction interaction between DNA and histone protein (Figure 1b). In this case, the chromatin exhibits more between DNA and histone protein (Figure1b). In this case, the chromatin exhibits more compacted compacted conformation [6]. Excessive histone deacetylation induced by HDAC can have a conformation [6]. Excessive histone deacetylation induced by HDAC can have a significant impact significant impact on the pathology of cancer via the silencing of tumor suppressor genes, including onp53. the pathologyFor instance, of the cancer more via the the chromatin silencing is conden of tumorsed, suppressor the fewer promoters genes, including of these p53.target For genes instance, are theaccessible more the to chromatin transcription is condensed, factors, whereas the fewer when promoters cells exhibit of these higher target HAT genes activity, are accessiblechromatin to transcriptionrelaxation is factors, associated whereas with when an increased cells exhibit transcri higherptional HAT activation activity, of chromatin tumor suppressor relaxation genes is associated [7,8]. withGiven an increased that dysregulation transcriptional of HDAC activation and/or of HAT tumor func suppressortion has genesbeen associated [7,8]. Given to thatcancer dysregulation etiology, of HDAC and/or HAT function has been associated to cancer etiology, intensive research is being conducted worldwide to develop HDAC inhibitors. In this review the role of HDAC and epigenetic Cancers 2019, 11, 850 3 of 29 Cancers 2019,