Cytosine Moiety Research Articles

Hydrogen-bonded cytosine-endowed supramolecular polymeric nanogels: Highly efficient cancer cell targeting and enhanced therapeutic efficacy

We demonstrate that cytosine moieties within physically cross-linked supramolecular polymers not only manipulate drug delivery and release, but also confer specific targeting of cancer cells to effectively enhance the safety and efficacy of chemotherapy—and thus hold significant potential as a new perspective for development of drug delivery systems. Herein, we successfully developed physically cross-linked supramolecular polymers (PECH-PEG-Cy) comprised of hydrogen-bonding cytosine pendant groups, hydrophilic poly(ethylene glycol) side chains, and a hydrophobic poly(epichlorohydrin) main chain. The polymers spontaneously self-assemble into a reversibly hydrogen-bonded network structure induced by cytosine and directly form spherical nanogels in aqueous solution. Nanogels with a high hydrogen-bond network density (i.e., a higher content of cytosine moieties) exhibit outstanding long-term structural stability in cell culture substrates containing serum, whereas nanogels with a relatively low hydrogen-bond network density cannot preserve their structural integrity. The nanogels also exhibit numerous unique physicochemical characteristics in aqueous solution, such as a desirable spherical size, high biocompatibility with normal and cancer cells, excellent drug encapsulation capacity, and controlled pH-responsive drug release properties. More importantly, in vitro experiments conclusively indicate the drug-loaded PECH-PEG-Cy nanogels can selectively induce cancer cell-specific apoptosis and cell death via cytosine receptor-mediated endocytosis, without significantly harming normal cells. In contrast, control drug-loaded PECH-PEG nanogels, which lack cytosine moieties in their structure, can only induce cell death in cancer cells through non-specific pathways, which significantly inhibits the induction of apoptosis. This work clearly demonstrates that the cytosine moieties in PECH-PEG-Cy nanogels confer selective affinity for the surface of cancer cells, which enhances their targeted cellular uptake, cytotoxicity, and subsequent induction of programmed cell death in cancer cells.

Novel 1, 2, 3-triazolic compounds derived from cytosine: Synthesis, spectroscopic characterization, in vitro antimicrobial activity and molecular docking studies

The development of novel antimicrobial drugs is crucial due to the increasing problem of antibiotic resistance. A new series of 1,4-disubstituted-1,2,3-triazole derivatives containing a cytosine moiety (3a, 3b, 3c and 3d) were synthesized using 1,3-dipolar cycloaddition in a mixture of ethanol and water under Cu(I)-catalyzed with N-alkyl: 1-(prop-2-ynyl)-4-amino-2-oxopyrimidine 2 as dipolarophiles and azide derivatives (sucre-azoture) as dipoles. The desired products were obtained in good yields by reacting with a catalytic amount of copper (II) sulfate and sodium ascorbate. The structure of these compounds was analyzed and characterized using spectroscopic measurements such as 1H NMR, 13C NMR, and mass spectroscopy. Encouragingly, all cycloaddition molecules exhibited promising activity against various bacterial strains including Staphylococcus aureus and Escherichia coli. The crystal structure modeling of protein 7AZ5 demonstrated strong binding affinities through hydrogen bonds with these molecules. The cycloaddition compounds displayed the highest binding energies in terms of antimicrobial efficacy. This suggests that these substances could serve as an effective model for the development and production of new and potent antimicrobial agents.

Inhibition of cytosine 5-hydroxymethylation during progression of cancer precursor lesions in the uterine cervix.

Methylation and hydroxymethylation of cytosine moieties in CpG islands of specific genes are epigenetic processes shown to be involved in the development of cervical (pre)neoplastic lesions. We studied global (hydroxy)methylation during the subsequent steps in the carcinogenic process of the uterine cervix by using immunohistochemical protocols for the detection of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in paraffin-embedded tissues of the normal epithelia and (pre)malignant lesions. This approach allowed obtaining spatially resolved information of (epi)genetic alterations for individual cell populations in morphologically heterogeneous tissue samples. The normal ectocervical squamous epithelium showed a high degree of heterogeneity for both modifications, with a major positivity for 5-mC in the basal and parabasal layers in the ectocervical region, while 5-hmC immunostaining was even more restricted to the cells in the basal layer. Immature squamous metaplasia, characterized by expression of SOX17, surprisingly showed a decrease of 5-hmC in the basal compartments and an increase in the more superficial layers of the epithelium. The normal endocervical glandular epithelium showed a strong immunostaining reactivity for both modifications. At the squamocolumnar junctions, a specific 5-hmC pattern was observed in the squamous epithelium, resembling that of metaplasia, with the typical weak to negative reaction for 5-hmC in the basal cell compartment. The reserve cells underlying the glandular epithelium were also largely negative for 5-hmC but showed immunostaining for 5-mC. While the overall methylation status remained relatively constant, about 20% of the high-grade squamous lesions showed a very low immunostaining reactivity for 5-hmC. The (pre)malignant glandular lesions, including adenocarcinoma in situ (AIS) and adenocarcinoma showed a progressive decrease of hydroxymethylation with advancement of the lesion, resulting in cases with regions that were negative for 5-hmC immunostaining. These data indicate that inhibition of demethylation, which normally follows cytosine hydroxymethylation, is an important epigenetic switch in the development of cervical cancer.

Supramolecular self-assembly of cytidine monophosphate-di-copper building blocks

We report the synthesis and characterization of three di-copper compounds, [Cu2phen2CMP(µ-OH)(µ-X)]·3H2O (with X = Cl− (1) and Br− (2)) and [Cu2phen2CMP(µ-OH)(µ-NO3)]·[Cu2phen2CMP(µ-OH)(NO3)]·7H2O (3). 1 and 3 present a dinuclear core assembled by an unusual bis-monodentate phosphate and µ2-hydroxo double bridge, further supported by bridging anions. The spontaneous self-assembly of an extended coordination structure of higher dimensionality, although possible in principle, has been hindered by the use of strongly coordinating counterions (Cl−, Br−) and, unexpectedly, even by the less coordinating nitrate ions. The neutral complexes feature unsaturated coordination sites, having both the N(3) and O(2) of the cytosine moieties of the CMP ligands still available for coordination. π···π Stacking and hydrogen bonding interactions established between the discrete chiral entities mainly drive the self-assembling of a 3D supramolecular network. Small hydrophilic voids are defined within the 3D net, which are filled by solvent water molecules. These small nuclearity complexes with coordinatively unsaturated CMP ligands are likely to act as tectons. They could be used as complex-as-ligands for further binding additional metal ions in a predictable manner, favoring a more rational synthetic approach aimed to a stricter structural and chemical control of the resulting material.

Photoreactive Cytosine-Functionalized Self-Assembled Micelles with Enhanced Cellular Uptake Capability for Efficient Cancer Chemotherapy.

Design, fabrication, and control of photoreactive supramolecular macromers─which are composed of a thermoresponsive polymer backbone and photoreactive nucleobase end-groups─to achieve the desired physical-chemical performance and provide the high efficiency required for chemotherapy drug delivery purposes still present challenges. Herein, a difunctional cytosine-terminated supramolecular macromer was successfully obtained at high yield. UV-irradiation induces the formation of cytosine photodimers within the structure. The irradiated macromer can self-assemble into nanosized spherical micelles in water that possess a number of interesting and unique features, such as desired micellar size and morphology, tunable drug-loading capacity, and excellent structural stability in serum-containing medium, in addition to well-controlled drug-release behaviors in response to changes in environmental temperature and pH; these extremely desirable, rare features are required to augment the functions of polymeric nanocarriers for drug delivery. Importantly, a series of in vitro studies demonstrated that photodimerized cytosine moieties within the drug-loaded micelles substantially enhance their internalization and accumulation inside cells via endocytosis and subsequently lead to induction of massive apoptotic cell death compared with the corresponding nonirradiated micelles. Thus, this newly developed "photomodified" nanocarrier system could provide a potentially fruitful route to enhance the drug delivery performance of nanocages without the need to introduce targeting moieties or additional components.

Mixed monolayer of a nucleolipid and a phospholipid has improved properties for spectroelectrochemical sensing of complementary nucleobases

A mixed monolayer of 1,2-dipalmitoyl-sn-glycero-3-(cytidine diphosphate) nucleolipid (DG-CDP) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was transferred from the air–water interface onto an gold (1 1 1) electrode surface using the Langmuir-Schaeffer (horizontal touch) technique. Compression isotherms were recorded for the monolayer spread at the air–water interface. These measurements demonstrated that the mixture composition 7:3 of DG-CDP:DPPC displayed reduced repulsive interactions between polar heads and ideal packing of acyl chains. Chronocoulometric experiments were performed to demonstrate stability of this film at the gold–solution interface. Photon polarization modulation infrared reflection absorption spectroscopy showed that the tilt angle of the acyl chains is slightly higher, and the chains are less twisted in the mixed than in the pure nucleolipid monolayer. In the mixed film, the tilt of the cytosine moiety (the sensing element of the monolayer) assumes a large angle with respect to the surface normal, even when the monolayer becomes detached from the gold surface. The mixed monolayer has improved properties for future applications for detection of guanine, its complementary base.

Electrostatics affects formation of Watson-Crick complex between DNA bases in monolayers of nucleolipids deposited at a gold electrode surface

Chronocoulometry was applied to determine charge in a monolayer of nucleolipid (1,2-dipalmitoyl-sn‑glycero-3-(cytidine diphosphate)) deposited at a gold electrode surface. The immersion method was used to measure the potential of zero charge of the interface (Epzci), which is a sum of charge on the monolayer of the nucleolipid and charge on the gold surface. Photon polarization infrared reflection absorption spectroscopy (PM-IRRAS) was used to determine formation of the Watson-Crick complex between terminal cytidine moiety of the nucleolipid and guanine (its complementary base) added to the solution. The combination of electrochemical and spectroscopic studies allowed one to demonstrate that the Watson-Crick complex is formed when the interface is positively charged. The potential applied to the electrode affects not only the complex formation but also orientation of the cytosine moiety. The complex is formed when the cytosine moiety is oriented assuming a small angle with respect to the electrode surface.

Dramatic changes in the electrochemical and spectroscopic behavior of DNA fragments induced by the loss of a single nucleotide

In this paper, the d(GCGAAGC) heptamer and the closely related d(GCGAGC) hexamer are examined via electrochemical (cyclic voltammetry) and spectroscopic (circular dichroism) methods. Dramatic changes in the CD spectroscopic and CV electrochemical properties, induced by the loss of only one single nucleotide (A), are detected. The CD spectra and native polyacrylamide gel electrophoresis (PAGE) confirmed structural changes taking place in the relevant chain-like oligodeoxynucleotide assemblies. Dedicated studies suggest that the heptamer (Hp) possesses a hairpin structure, whereas the hexamer (Hx) appears to be rather a duplex. Both of the structures exhibited completely different adsorption behavior at the hanging mercury drop electrode, and this factor was readily confirmed by means of elimination voltammetry with linear scan (EVLS). We established that the Hp hairpin (~−1300 mV), compared to the Hx duplex (~−1360 mV), is the thermodynamically favored electron acceptor. The adsorption isotherms were constructed based on the voltammetric peak height values, reflecting the reduction of the adenine (A) and cytosine (C) moieties as well as the oxidation of the 7,8-dihydroguanine (7,8-DHG) moieties. Finally, as revealed by the spectroscopic and electrochemical results, Hx forms a bimolecular antiparallel homo-duplex carrying both Watson–Crick base pairs (CG or GC) and mismatched edge-to-edge base pairs (GA or AG).

Synthesis of Tritium-Labeled Non-Natural Analogs of Purine and Pyrimidine Nucleosides

Convenient preparative ways to synthesize tritium-labeled non-natural derivatives containing the cytosine and guanine moieties have been developed. The main distinction of these compounds from those already known consists in that they contain a chiral center. The tritium-labeled 2'-desoxy-3'-oxacytidine can was synthesized by the reaction of catalytic dehalogenation in solution of the corresponding 5-bromine-substituted compound; for 6-aminocyclopropyl-2'-desoxy-3'-oxaguanosine, the reaction of catalytic heterogeneous catalytic exchange in solution was used; for rest of compounds, the reaction of solid-phase catalytic hydrogenation (SCH) was employed.

Molecular recognition between guanine and cytosine-functionalized nucleolipid hybrid bilayers supported on gold (111) electrodes

A hybrid bilayer lipid membrane (hBLM), constructed with a 1-hexadecanethiol self-assembled interior leaflet and a 1,2-dipalmitoyl-sn-glycero-3-cytidine nucleolipid exterior leaflet, was deposited at the surface of a gold (111) electrode. This system was used to investigate the molecular recognition reaction between the cytosine moieties of the lipid head group with guanine molecules in the bulk electrolyte solution. Electrochemical measurements and photon polarization modulation infrared reflection absorption spectroscopy (PMIRRAS) were employed to characterize the system and determine the extent of the molecular recognition reaction. The capacitance of the hBLM-covered gold electrode was very low (~1 μF cm−2), therefore the charge density at the gold surface was small. Changing the electrode potential had a minimal effect on the complexation between the cytosine moieties and guanine molecules due to small changes in the static electric field across the membrane. This behavior favored the formation of the guanine–cytosine complex.

Triplet-Induced Lesion Formation at CpT and TpC Sites in DNA.

UV irradiation induces DNA lesions particularly at dipyrimidine sites. Using time‐resolved UV pump (250 nm) and mid‐IR probe spectroscopy the triplet pathway of cyclobutane pyrimidine dimer (CPD) formation within TpC and CpT sequences was studied. The triplet state is initially localized at the thymine base but decays with 30 ns under formation of a biradical state extending over both bases of the dipyrimidine. Subsequently this state either decays back to the electronic ground state on the 100 ns time scale or forms a cyclobutane pyrimidine dimer lesion (CPD). Stationary IR spectroscopy and triplet sensitization via 2′‐methoxyacetophenone (2‐M) in the UVA range shows that the lesions are formed with an efficiency of approximately 1.5 %. Deamination converts the cytosine moiety of the CPD lesions on the time scale of 10 hours into uracil which gives CPD(UpT) and CPD(TpU) lesions in which the coding potential of the initial cytosine base is vanished.

Modulation of the induced π-stacking interactions between the active site cytosine moiety of HIV-integrase and inhibitors containing substituted-methylbenzene: Physical nature of the positional and substituent effects

Although the π-stacking interaction between the substituted aromatic ring of small molecule inhibitors and the cytosine nucleobase present at the active site of HIV integrase (IN) are abundantly seen, no current study systematically covers differing positional substituents. Herewith, we report a comprehensive and systematic study aimed at unraveling the nature of substituent effects on model C||X-MB-Y (|| denotes π-stacking interaction, X is CHO, CN, NO2, COOH, Cl, SH, SCH3, F, NH2, OH, OCH3, CH3 and H; MB denotes methylbenzene and Y typifies diverse substituent positioning which includes m1, m2, o1, o2 and p) based on findings from the methodical incorporation of B3LYP-D3/6-311++G(d,p) binding energy (Ebind) as well as symmetry-adopted perturbation theory (SAPT) results. Energy data indicated that stability of the C||X-MB-Y complexes increased in the presence of both the electron-withdrawing substituents (EWSs) and electron-donating substituents (EDSs) relative to the unsubstituted ones (X = H). Moreso, the lack of a good correlation between Ebind and σmeta confirmed that the mechanism by which the various substituents facilitated the stability of each complex is not only by electrostatic interactions. In agreement with this finding, it was observed in this study that the combination of different substituent constant terms for all positions gave excellent correlations with Ebind. In addition, the results indicated that the strength of π-stacking interactions depends on the corresponding orientations of interacting rings. Also, it was observed that the most stable complexes for EWSs and EDSs corresponded to positions o1 and o2, respectively. Estimations of SAPT revealed the importance of the electrostatic term (Eele) in the prediction of Ebind for each position, except at position m2, where all energy components played important roles in the stability of the complexes. Also, comparative studies of the different positions indicated that the stability of the complexes decreases by a decreasing Eele.

Electric-Field-Driven Molecular Recognition Reactions of Guanine with 1,2-Dipalmitoyl-sn-glycero-3-cytidine Monolayers Deposited on Gold Electrodes

Monolayers of 1,2-dipalmitoyl-sn-glycero-3-cytidine were incubated with guanine in a 0.1 M NaF electrolyte at the surface of a Langmuir trough and transferred to gold (111) electrodes using the Langmuir-Schaefer technique. Chronocoulometry and photon polarization modulation infrared reflection absorption spectroscopy were employed to investigate the influence of the static electric field on the orientation and conformation of the cytidine nucleolipid molecules on the metal surface in the presence of guanine and to monitor the molecular recognition of guanine with the cytosine moiety. When the monolayer is exposed to guanine solutions, the cytosine moiety binds to the guanine residue in either a Watson-Crick complex at positively charged electrode surfaces or a noncomplexed state at negative surface charges. The positive electrostatic field causes the cytosine moiety and the cytosine-guanine complex to adopt a nearly parallel orientation with respect to the plane of the monolayer with a measured tilt angle of ∼10°. The parallel orientation is stabilized by the interactions between the permanent dipole of the cytosine moiety or the Watson-Crick complex and the static electric field. At negative charge densities, the tilt of the cytosine moiety increases by ∼15-20°, destabilizing the complex. Our results demonstrate that the static electric field has an influence on the molecular recognition reactions between nucleoside base pairs at the metal-solution interface and can be controlled by altering the surface charge at the metal.

Spectroelectrochemical Characterization of 1,2-Dipalmitoyl- sn-glycero-3-cytidine Diphosphate Nucleolipid Monolayer Supported on Gold (111) Electrode.

The effect of the electrode potential on the orientation and conformation of the 1,2-dipalmitoyl- sn-glycero-3-cytidine monolayer deposited on a gold (111) electrode surface was described. The potential of zero free charge ( Epzc) for the monolayer-covered electrode was determined to be -0.2 V vs SCE. The differential capacitance and charge density data indicated that the monolayer is stable at the electrode surface when ( E - Epzc) > 0.0 V. At negative rational potentials, a progressive detachment (electrodewetting) of the monolayer occurs. The monolayer is fully detached from the electrode surface at ( E - Epzc) < -0.6 V. The conformation and orientation of the acyl chains and the orientation of the cytosine moiety were determined with the help of photon polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). The IR measurements demonstrate that the acyl chains are predominantly in the gel phase in the adsorbed state and tilted at an angle of ∼30° with respect to the electrode surface normal. The tilt angle of the acyl chains increases when the film is detached from the gold surface, indicating that the monolayer becomes more disordered. At ( E - Epzc) > 0.0 V, the plane of the cytosine moiety assumes a small angle of ∼20° with respect to the surface. At negative potentials, the tilt angle of the cytosine fragment increases and rotates. With the help of DFT calculations, these changes were explained by the repulsion of the positive pole of the cytosine permanent dipole moment by the positively charged gold surface and its attraction to the metal surface at negative electrode potentials. This work provides unique information for the future development of sensors based on the molecular recognition of nucleoside targets.

Silver Ions Detection via Nucleolipids Self-Assembly.

A novel hybrid bioinspired amphiphile featuring a cytosine moiety, which self-assembles into liposomes can be used to detect silver ions in aqueous media. The coordination of Ag+ ions by the nucleotide moiety increases membrane rigidity, which enhances the fluorescence of a common reporter, Thioflavin T. Ag+ can be sensed even at trace concentrations (3 ppb) with great specificity over other metals ions. These nucleotide based supramolecular structures can be used to detect silver ions in drinking water, demonstrating the robustness of this approach.

Hydrolysis of the non-canonical cyclic nucleotide cUMP by PDE9A: kinetics and binding mode.

The non-canonical cyclic nucleotide cUMP and the phosphodiesterase PDE9A both occur in neuronal cells. Using HPLC-coupled tandem mass spectrometry, we characterized the kinetics of PDE9A-mediated cUMP hydrolysis. PDE9A is a low-affinity and high-velocity enzyme for cUMP (Vmax = ~ 6μmol/min/mg; Km = ~ 401μM). The PDE9 inhibitor BAY 73-6691 inhibited PDE9A-catalyzed cUMP hydrolysis (Ki = 590nM). Docking studies indicate two H-bonds between the cUMP uridine moiety and Gln453/Asn405 of PDE9A. By contrast, the guanosine moiety of cGMP forms three H-bonds with Gln453. cCMP is not hydrolyzed at a concentration of 3μM, but inhibits the PDE9A-catalyzed cUMP hydrolysis at concentrations of 100μM or more. The probable main reason is that the cytosine moiety cannot act as H-bond acceptor for Gln453. A comparison of PDE9A with PDE7A suggests that the preference of the former for cGMP and cUMP and of the latter for cAMP and cCMP is due to stabilized alternative conformations of the side chain amide of Gln453 and Gln413, respectively. This so-called glutamine switch is known to be involved in the regulation of cAMP/cGMP selectivity of some PDEs.

Structural insights into the specificity and catalytic mechanism of mycobacterial nucleotide pool sanitizing enzyme MutT2

Mis-incorporation of modified nucleotides, such as 5-methyl-dCTP or 8-oxo-dGTP, in DNA can be detrimental to genomic integrity. MutT proteins are sanitization enzymes which function by hydrolyzing such nucleotides and regulating the pool of free nucleotides in the cytoplasm. Mycobacterial genomes have a set of four MutT homologs, namely, MutT1, MutT2, MutT3 and MutT4. Mycobacterial MutT2 hydrolyzes 5 m-dCTP and 8-oxo-dGTP to their respective monophosphate products. Additionally, it can hydrolyze canonical nucleotides dCTP and CTP, with a suggested role in sustaining their optimal levels in the nucleotide pool. The structures of M. smegmatis MutT2 and its complexes with cytosine derivatives have been determined at resolutions ranging from 1.10 Å to 1.73 Å. The apo enzyme and its complexes with products (dCMP, CMP and 5 m-dCMP) crystallize in space group P21212, while those involving substrates (dCTP, CTP and 5 m-dCTP) crystallize in space group P21. The molecule takes an α/β/α sandwich fold arrangement, as observed in other MutT homologs. The nucleoside moiety of the ligands is similarly located in all the complexes, while the location of the remaining tail exhibits variability. This is the first report of a MutT2-type protein in complex with ligands. A critical interaction involving Asp116 confers the specificity of the enzyme towards cytosine moieties. A conserved set of enzyme-ligand interactions along with concerted movements of important water molecules provide insights into the mechanism of action.

Inhibitor selectivity of CNTs and ENTs

The concentrative nucleoside transporters (CNT; solute carrier family 28 (SLC28)) and the equilibrative nucleoside transporters (ENT; solute carrier family 29 (SLC29)) are important therapeutic targets but may also mediate toxicity or adverse events.To explore the relative role of the base and the monosaccharide moiety in inhibitor selectivity we selected compounds that either harbor an arabinose moiety or a cytosine moiety, as these groups had several commercially available drug members.The screening data showed that more compounds harboring a cytosine moiety displayed potent interactions with the CNTs than compounds harboring the arabinose moiety. In contrast, ENTs showed a preference for compounds with an arabinose moiety.The correlation between CNT1 and CNT3 was good as five of six compounds displayed IC50 values within the threefold threshold and one displayed a borderline 4-fold difference. For CNT1 and CNT2 as well as for CNT2 and CNT3 only two of six IC50 values correlated and one displayed a borderline 4-fold difference. Interestingly, of the six compounds that potently interacted with both ENT1 and ENT2 only nelarabine displayed selectivity.Our data show differences between inhibitor selectivities of CNTs and ENTs as well as differences within the CNT family members.

Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors.

DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound 4 and its derivative 2 showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound 4 binds to the PRMT4 active site, displacing strongly the S-adenosyl-l-methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

Epigenetic Mechanisms and Events in Gastric Cancer-Emerging Novel Biomarkers.

Gastric cancer is one of the most common malignancy worldwide. The various genetic and epigenetic events have been found to be associated with its carcinogenesis. The epigenetic is a heritable and transient/reversible change in the gene expression that is not accompanied by modification in the DNA sequence. This event is characterized by the alteration in the promoter CpG island of the gene or histone modification. These events are associated with silencing of critical tumor suppressor gene and activation of oncogenes leading to carcinogenesis. The DNA methylation is a chemical change in the DNA sequence that most commonly occurs at cytosine moiety of CpG dinucleotide and histone, primarily on N- terminal tail that ultimately effect the interaction of DNA with chromatin modifying protein.Hypermethylation of tumor suppressor genes and global hypomethylation of oncogenes are widely studied epigenetic modifications. There are large number of publish reports regarding epigenetic events involving gastric cancer. These changes are potentially useful in identifying markers for early diagnosis and management of this lethal malignancy. Also, role of specific miRNAs and long non coding RNAs in regulation of gene expression is gaining interest and is a matter of further investigation. In this review, we aimed to summarize major epigenetic events (DNA methylation) in gastric cancer along with alteration in miRNAs and long non coding RNAs which plays an important role in pathology of this poorly understood malignancy.