Leveraging histone glycation for cancer diagnostics and therapeutics

Abstract

Cancer cells undergo metabolic reprogramming to rely mostly on aerobic glycolysis (the Warburg effect). The increased glycolytic intake enhances the intracellular levels of reactive sugars and sugar metabolites. These reactive species can covalently modify macromolecules in a process termed glycation. Histones are particularly susceptible to glycation, resulting in substantial alterations to chromatin structure, function, and transcriptional output. Growing evidence suggests a link between dysregulated metabolism of tumors and cancer proliferation through epigenetic changes. This review discusses recent advances in the understanding of histone glycation, its impact on the epigenetic landscape and cellular fate, and its role in cancer. In addition, we investigate the possibility of using histone glycation as biomarkers and targets for anticancer therapeutics.

Regulation of gene expression by chromatin modifications

Gene expression, and ultimately, the cell fate of eukaryotic cells are regulated by chromatin (see Glossary). Regulation of chromatin, which comprises histones and DNA, is in part executed by chemical modifications of both components, termed epigenetics [1]. Disruption of these epigenetic patterns is often associated with abrogated biological function and cellular transformation [2–4]. Of those, histones are particularly susceptible to post-translational modifications (PTMs) on their flexible N-terminal tails, which contain a high concentration of basic amino acids [5]. Importantly, the combination of these modifications acts as a dynamic platform for gene regulation [6]. PTMs can directly disrupt the electrostatic interaction between the positively charged histone tails and the negatively charged DNA backbone or change the recruitment of effector proteins that exert a function on chromatin [5, 7]. For this reason, PTMs are highly regulated and abrogation to the enzymes that “write” and “erase” these marks often leads to cellular transformation and cancer [2, 3].

Besides the well-studied enzymatically-installed PTMs, reactive species can covalently react with DNA and proteins to introduce non-enzymatic covalent modifications (NECMs) [8]. Glycation is one of the most well-studied NECMs where reactive groups of uptaken reducing sugars, their derivatives, and downstream metabolic by-products react with nucleophilic protein side chains and nucleobases, often via the Maillard reaction [9]. The glycation rate varies depending on the local concentration and the reactivity of the involved chemical moieties [10]. The early, often unstable glycation adducts can further oxidize, rearrange, cyclize and cross-link, yielding a diverse array of more stable adducts termed advanced glycation end products (AGEs) [11, 12]. AGEs accumulate over time and are directly correlated with changes in the local metabolic state or oxidative stress [13]. Glycation can lead to protein inactivation and dysfunction [14] and was found to correlate with several diseases such as diabetes and Alzheimer’s disease [15, 16].

In recent years, a growing emphasis has been put on the role of glycation in cancer development and progression where cell metabolism is shifted to aerobic glycolysis (the Warburg effect) leading to an increased glycolytic flux and a higher rate of glycation [17–19]. While lower rates of glycation are reported to increase gene expression and might be beneficial for cancer progression [20, 21], histone glycation occurs in cancer cells at a higher rate leading to cell death and transcription suppression due to the cytotoxicity of the formed AGEs [22, 23]. Therefore, multiple cellular mechanisms have evolved to either prevent the accumulation of reactive molecules or reverse glycation adducts to reduce the negative effects of AGE accumulation [24, 25]. Such defense mechanisms are especially upregulated in various cancer cells in order to counter the unusually high glycolysis rates and thus present a new vulnerability of these cells (Figure 1A) [26]. In this review we mainly focus on histone damage by the dicarbonyl metabolic by-product methylglyoxal (MGO), as one of the more reactive and well-studied metabolites that was shown to exist in particularly high concentration in cancer cells (up to 350 μM compared with 0.5–1.5 μM in normal cells) [27, 28] leading to the formation of AGEs such as hydroimidazolones or N(2)-(1-carboxyethyl)-2’-deoxyguanosine (CEdG) (Figure 2) [29, 30]. MGO modifications have emerged as a prominent glycation event on histones, present at comparable levels as certain canonical PTMs [31]. Here, we specifically highlight the recent advances in MGO-induced histone glycation, its impact on chromatin landscape, and potential role in cancer progression. We also showcase how histone glycation might offer a new avenue for cancer diagnostics and therapeutics.

Figure 1. Histone glycation links metabolic reprogramming with epigenetic control in cancer.

(A) The increased glycolytic flux in cancer cells can lead to a higher level of glycation adducts on histones compared to premalignant cells. Several defense mechanisms are upregulated to reverse glycation on histones and maintain normal post-translational modification (PTM) patterns. Glyoxalase and deglycases have been described to scavenge MGO or remove glycation adducts from proteins and DNA. Inhibitors of the deglycation repair mechanism can be utilized to target cancer cells by inducing glycation-related cell death. (B) Glycation disrupts the normal PTM patterns by competing with enzymatic PTMs, changes the electrostatic interactions between DNA and histones, induces cross-linking, and alters the 3D structure and surface topology.

Figure 2. Mechanism of methylglyoxal-induced glycation on lysine, arginine, and guanine.

Selected reactions of histone residues (arginine and lysine) and DNA moieties (guanosine) with MGO leading to early glycation adducts. The early glycation products can undergo further dehydration, rearrangements and cross-linking reactions to form more stable advanced glycation end products (AGEs).

Histone Glycation and its effects on chromatin structure

MGO is a highly reactive dicarbonyl molecule that is formed as a by-product of the glycolysis pathway [32]. MGO reacts with deoxyguanine in DNA resulting in DNA strand breaks, mutations, and cross-links between DNA and proteins [33, 34] (Figure 2). In addition, MGO preferentially reacts with arginine and, to a lesser extent, with lysine residues in proteins [31] (Figure 2). This makes histones a prime target of MGO due to their high number of reactive arginine and lysine side chains at their N-terminal tails. In addition, histones are long-lived and are susceptible to accumulating glycation damage over time [35]. Histone MGO-glycation was shown to be prevalent in breast cancer cell lines, xenografts, and breast cancer patient tumors and is reported to affect cellular proliferation [36]. This glycation occurs primarily on core histone H3, while the other histones, H4, H2B, and H2A are modified to a lesser extent [36]. Complementary studies using metabolic labeling indicated that not only the nucleophilic histone tails but also arginine residues near the DNA binding site are modified by MGO [31].

Growing evidence indicates that MGO-glycation on histones interferes with the epigenetic landscape and alters cellular fate by various mechanisms (Figure 1B): 1) Glycation adducts can directly compete with enzymatically-introduced PTMs on arginines and lysines (e.g. replacement of methylation with glycation adducts) [37]. 2) Low doses or short exposure times of MGO lead to chromatin decompaction and transcription upregulation as MGO neutralizes the positive charge of the side chain and disrupts the interaction with the negatively charged DNA in a similar matter to the well-known histone acetylation[36]. 3) High doses or long exposure times of MGO, which are proposed to mimic the increased rate of glycolysis in cancer cells, lead to chromatin compaction and transcription suppression by inducing histone-histone and histone-DNA crosslinking [36]. 4) Histone glycation can lead to altered 3D topology due to protein aggregation [38].

In addition to MGO, several other sugar and metabolic by-products have been shown to glycate histones. Yet, their biological impact remains sparsely studied. Glyoxal (GO), a close relative of MGO, consists of a similar reactive dicarbonyl group and has been reported to modify core histones similarly to MGO [39, 40]. Another dicarbonyl species, 3-deoxyglucosone (3-DG), was reported to form AGE on the linker histone H1, which disrupts its secondary structure [41]. Monosaccharides such as glucose and ribose can glycate histones, albeit at a slower rate than dicarbonyls as they are in an equilibrium between the “open-linear” and “closed-ring” forms. The reactive carbonyl needed for the Maillard reaction is only available in the less dominant “open” form reducing their reactivity [42, 43]. Other sugar derivatives such as ADP ribose have been shown to glycate core and linker histones to a biologically significant degree [44].

Analytical methods to understand glycation events on histones

The analysis of glycation products on histones is challenging. Traditionally, Histone glycation is characterized by mass spectrometry or antibody-based immunological assays (primarily Western Blotting) [31, 36]. Antibodies against glycation have been widely deployed in the discovery of protein glycation, but face some challenges. Generating antibodies against early glycation modifications is difficult as many early glycation adducts can rearrange into a mixture of chemical structures and are most likely not stable enough under physiological conditions to inoculate animals for weeks which can lead to a loss of specificity of the antibody. However, the pan antibody against MGO and antibodies against stable AGEs, such as carboxyethyl lysine (CEL) and carboxymethyl lysine (CML), are commercially available. To detect distinct advanced glycation marks, chemically synthesized peptides with a set of relatively stable MGO arginine modifications have been used to generate antibodies which recognize specific isomers of the methylglyoxal hydroimidazolones [45], offering a new route for more selective antibodies.

Mass spectral analysis has been used to study enzymatic PTMs on histones, yet the analysis of glycation adducts on histones by mass spectrometry has several challenges. Firstly, the glycation adducts consist of a wide array of early unstable glycation products and advanced glycation adducts from rearrangements and cross-links. These modifications are often too many to target during analysis, especially on histones containing a high number of PTMs. Next, glycation occurs mostly on arginine and lysine, preventing digestion with trypsin and leading to products too long for separation by chromatography. During MS analysis, glycation decreases the net charge on the modified residues limiting their ionization and detection in the mass spectrum. In addition, the early glycation adducts are often not stable and sample preparation, such as propionylation, high temperature or acid-based histone extraction, might alter their structure. To bridge this gap, new chemical probes and proteomics approaches are being developed to track glycation and better understand its biological function in a site-specific matter [31, 40, 42, 46, 47].

Glycation as biomarkers in cancer

The early detection of cancer, the prediction of the clinical outcome, the response to chemotherapeutic agents, and the risk of metastasis are important diagnostic tools for better cancer treatment, yet finding suitable tumor biomarkers remains challenging. Monitoring the changes in epigenetic marks has been proposed as potential biomarkers for the prediction of cancer outcomes [48, 49]. As glycation marks on H3 are elevated in patient tumor samples compared to non-tumor samples from the same patients’ [36], analysis of the glycation pattern on histones and glycation-associated molecules might offer a new path for cancer diagnostics.

Indeed, glycated proteins are long used as clinical biomarkers in disease: traditionally, Type 2 diabetes mellitus is diagnosed and monitored by measuring glycation adducts on plasma proteins by immunoassays or chromatography [50, 51].

The plasma levels of carboxymethyl lysine are associated with an increased risk of prostate cancer and have been suggested as potential biomarkers [52]. Similarly, monitoring glycation marks on H3, such as the H3R53, might help in the early diagnosis of cancer [31]. Yet, the exact glycation adducts of histones that predict the onset of cancer are still unknown and further analysis of the histone glycation patterns in cancer patient cells is necessary to evaluate glycation adducts as markers for cancer.

Another suggested approach to predict cancer progression is the use of auto-antibodies of cancer patients against glycated histones [53, 54]. Mir et al. showed that patients suffering from various cancers develop a strong immune response against histone glycation, offering a new path to predict cancer at an early stage [53]. However, a deeper understanding of these auto-antibodies and their role in predicting and monitoring tumor progression is needed to exploit their full potential. In addition, several glycation defense systems, such as DJ-1 and GLO1 (see Repair Mechanisms) are upregulated in cancer and are therefore proposed as biomarkers [55–58]. Recently, Chen et al. showed that DJ-1 levels correlate with the tumor-node-metastasis stage in serum and tissue of colorectal cancer patients [57]. Measuring DJ-1 levels in patients might offer a new route to monitoring metastasis in cancer patients. Yet, further research into these defense mechanisms and their role in mitigating glycation are necessary for the use of DJ-1 and other glycation defense systems as markers for tumor progression.

Repair mechanisms

To prevent the deleterious accumulation of glycation adducts on histones and therefore maintain a functional epigenetic landscape, various enzymatic mechanisms have evolved to 1) directly scavenge free reactive sugar molecules and 2) remove early glycation adducts.

Glyoxalase defense system (GLO1, GLO2)

The most prominent cellular detoxifying strategy are the glyoxalases that have been shown to scavenge MGO and convert it into the more inert D-lactate. The glyoxalase system is comprised of two enzymes, glyoxalase 1 (GLO1) and glyoxalase 2 (GLO2). Mechanistically, after MGO spontaneously reacts with glutathione (GSH) to form a hemithioacetal intermediate, it is then converted to the thioester S-D-lactoylglutathione by GLO1. S-D-lactoylglutathione is then hydrolyzed to the end product, D-lactate, by GLO2. GLO1, the key rate-limiting enzyme in this cascade, is overexpressed in many cancers, probably to meet the increased need for detoxification of sugar metabolites required to sustain growth and avoid MGO-induced apoptosis [58–60]. Overexpression of GLO1 has also been directly correlated with poor survival outcome in breast cancer patients and tumor multidrug resistance in cancer chemotherapy [61].

DJ-1

DJ-1 (also known as PARK7, Parkinson disease protein 7) is a small (189 residues) but multifunctional protein shown to protect cells from reactive oxygen species and metabolic damage [62, 63]. In the context of glycation defense, DJ-1 has been characterized both as a glyoxalase, removing free MGO like GLO1/2 [64, 65], and a deglycase, directly removing early MGO adducts on proteins and nucleic acids to repair glycation damage [31, 36, 66, 67]. Despite the ongoing debate on whether the substrate of DJ-1 is free reactive carbonyls or glycated biopolymers [68], DJ-1 plays a significant physiological role in cancer and is crucial for maintaining a lower level of metabolic stress to evade cell death. Indeed, DJ-1 is highly expressed in many cancers and is used as a reliable biomarker for tumor aggressiveness and survival outcome in cancer patients [55–57].

PAD4

Protein arginine deiminase 4 (PAD4) catalyzes the citrullination of arginine residues on proteins [69, 70] including histones [71–73]. Interestingly, PAD4 was found to be overexpressed in the blood of patients with malignant tumors [74]. Recently, PAD4 was discovered to antagonize the formation of MGO adducts on histone by competing for the reactive arginine sites and by converting early MGO-glycated arginines into citrulline [37].

FN3K

Fructosamine-3-kinase (FN3K) is a sugar kinase that catalyzes the phosphorylation of the C-3 hydroxyl group on the attached sugar, leading to the destabilization and subsequent removal of the glycation adduct [75, 76]. FN3K has been found to play a key role in NRF2-driven lung and liver cancers by deglycating sugar adducts on NRF2 and therefore activating its oncogenic activity [77]. However, due to its mitochondrial and cytosolic subcellular localization, FN3K can only repair glycated histones during and after translation and is unable to attenuate nuclear histone glycation damage [42, 78]. Nevertheless, FN3K plays an important role in the progression of many cancer types and is a candidate therapeutic target for inducing metabolic stress in cancers.

Glycation as a target for anticancer drugs

Given the highly glycolytic nature of many cancer cells, glyoxalases and other deglycases are often overexpressed to attenuate glycation damage in the cell to avoid glycation-induced cell death. Therefore, several small molecules (Table 1) have been developed to specifically inhibit the glycation repair mechanism and render tumor cells vulnerable to the accumulation of cytotoxic glycation adducts.

Table 1.

List of inhibitors for glycation repair and detoxification systems with possible cancer applications

Target	Entry number	Inhibitor	Cancer applications	Refs
GLO1	1	S-p-Bromobenzylglutathione cyclopentyl diester	Induced MGO accumulation to inhibit cancer cell growth and promote cancer cell apoptosis Active against breast, brain, lung, colon, leukemia, melanoma, ovarian, renal, prostate cancer cell lines Active against glioblastoma tumors in mice	[79–83]
	2	Methotrexate	Inhibited MGO metabolism in patients with lymphoid leukemia FDA-approved chemotherapeutic drug	[84]
	3	Curcumin and derivatives	Potent competitive GLO1 inhibitor Active against breast, prostate and brain cancer cell lines	[85, 86]
	4	Tetrahydropyridoindole-thiourea scaffold	Increased intracellular MGO level in lung cancer cells Suppressed osteoclast formation in mouse macrophage cells	[87]
PAD4	5	F-amidine	Covalent inhibitor that targets the active site cysteine	[88]
	6	GSK484	Reversible covalent inhibitor Blocked the formation of mouse neutrophil extracellular traps (NETs) Facilitated apoptosis of triple-negative breast cancer (TNBC) cells Sensitized irradiation-induced inhibition of TNBC	[89]
	7	BMS-P5	More potent than GSK484 Blocked NETs formation and hindered the progression of multiple myeloma in mice	[92]
	8	JBI-589	Blocked the formation of NETs, reduced both primary tumor growth and lung metastases in mice	[93]
DJ-1	9	Amino-epoxycyclohexenone	Irreversible covalent inhibitor targeting the active site cysteine	[94]
	10	Isatin-based analogs	Reversible covalent inhibitor targeting the active site cysteine	[95]

GLO1 inhibitors

Implicated in cancer progression and multidrug resistance in chemotherapy, GLO1 has been sought after as a potential therapeutic target for cancer therapy. It was shown that inhibition of GLO1 in tumor cells promotes MGO-induced apoptosis and improves chemotherapy outcome. One of the first GLO1 inhibitors, S-p-bromobenzylglutathione cyclopentyl diester (1 in Table 1), was shown to inhibit tumor growth and activate apoptosis by inducing the accumulation of intracellular MGO in human leukemia 60 (HL60) cells [79]. Further studies found 1 active against multiple cancer cell lines, including brain cancer, breast cancer, prostate cancer, lung, colon, renal, and ovarian cancer cell lines [26, 79–83]. Methotrexate (2 in Table 1), one of the most commonly used chemotherapeutic drugs, was shown to inhibit the metabolism of MGO in vivo in patients with lymphoid leukemia through its inhibitory activity against GLO1 [84]. Curcumin (3 in Table 1) and its derivatives are another class of small molecules that have been found to reduce GLO1 activity. Specifically, 3 was first shown to hinder the growth of breast cancer cells (JIMT-1, MDA-MB-231) by targeting GLO1 [85]. Further optimization of the curcumin scaffold using computational docking and modeling identified more potent GLO1 inhibitors [86]. More recently, a chemoproteomic profiling approach was adopted to screen a focused indole-containing small molecule library to identify a first-in-class mixed-type GLO1 inhibitor (4 in Table 1) that increased MGO levels in cells [87]. Since most GLO1 inhibitors discovered to date behave as competitive inhibitors, this mixed-type inhibitor offers a new avenue for designing GLO1 inhibitors.

PAD4 inhibitors

Several highly potent PAD4 inhibitors have been reported in recent years. Yuan et al. developed a fluoroacetamidine-based irreversible covalent inhibitor (5 in Table 1) of PAD4 by targeting the active site cysteine (Cys645), directly blocking the site of arginine citrullination [88]. GSK484 (6 in Table 1) is a reversible covalent inhibitor of PAD4 that has been shown to prevent the formation of neutrophil extracellular traps (NETs) [89], that have been shown to be associated with tumor progression and metastasis [90, 91]. In addition, Li et al. used a more potent PAD4 inhibitor developed by Bristol-Myers Squibb, BMS-P5 (7 in Table 1), to further validate that the pharmacological inhibition of PAD4 blocks NETs formation and slows down the progression of multiple myeloma in mice [92]. Most recently, another PAD4 inhibitor that shared a similar pharmacophore with 6 and 7, JBI-589 (8 in Table 1), was shown to suppress both primary tumor growth and lung metastases by preventing PAD4-mediated NETs formation [93]. Although potent and specific PAD4 inhibitors are commercially available, the therapeutic potential of using PAD4 inhibitors for the treatment of tumors with overexpressed deglycases has not yet been explored as most studies focused on the role of citrullination rather than deglycation by PAD4.

DJ-1 inhibitors

With cumulative evidence that many cancer cells are dependent on DJ-1 for survival and proliferation, several research groups have been working on the development of small molecule compounds that would inhibit DJ-1’s deglycase activity for the treatment of cancer. DJ-1’s catalytic cysteine residue (Cys106) is the key residue that influences many of its known functions and has been characterized extensively via crystallography, enzymology, and through covalent attachment. To date, two classes of compounds have been used to target DJ-1’s catalytic cysteine residues (Cys106). Drechsel et al. developed an epoxycyclohexenone scaffold (9) that leverages the irreversible covalent activity of the epoxide to target the catalytic cysteine [94]. The second class of inhibitors is based around an isatin core (10) providing reversible covalent interactions with Cys106. Tashiro et al. uncovered and optimized an isatin-based inhibitor of DJ-1 as well as published several of the key structural data that we and others have used to develop the program further [95]. Thereafter, Chen et al. sought to leverage DJ-1’s dimeric properties by lashing two isatin compounds together [96]. Finally, Maksimovic et al. developed a high-throughput fluorescence-based assay before evaluating and further optimizing the isatin compounds. Thereafter, the authors sought to shift away from the metabolic instability of the isatin scaffold and generate an even more potent DJ-1 inhibitor. To this end, they developed an irreversible covalent series which presents a great starting point for further development [97]. Although all the above-mentioned inhibitors were only recently developed and have not yet been tested for their effect on histone glycation, these present a promising anti-cancer therapeutic strategy by leveraging cancer cells’ dependence on DJ-1.

FN3K inhibitors

Although FN3K does not deglycate histones in the nucleus, its role in activating NRF2 through deglycation makes it a prime candidate for targeting NRF2-driven cancers. In comparison with other deglycases, the development of small molecule inhibitors targeting FN3K has been lacking. A synthetic fructosamine, 1-deoxy-1-morpholinofructose (DMF), has been used to inhibit FN3K in biochemical assays [98–100]. Another substrate mimic of fructoselysine, Dyn-12 (3-methylsorbitolysine), was reported to inhibit the enzymatic activity of FN3K [101]. However, neither of them has been tested in the context of cancer, and no novel FN3K inhibitor has been developed in recent years.

Concluding remarks and future perspectives

Cancer rates are growing at an alarming pace even in younger individuals [102]. Therefore, new diagnostic and therapeutic tools are necessary for improved cancer detection and treatment. One significant difference between healthy and cancer cells is the increase in glycolytic flux which leads to abnormally high levels of reactive sugar and sugar by-products in cancer cells [17, 103, 104]. The generated electrophilic species can covalently react with various macromolecules, including proteins. The resulting modifications can interfere with the naturally occurring PTM pattern and change the stability, structure, and function of the modified proteins. Histones are particularly prone to accumulate NECMs as they are long-lived and harbor many nucleophilic residues. Thus, several cellular responses against glycation are upregulated in cancer, and inhibition of these defense systems is therefore proposed to have anti-tumor effects [58, 66, 97].

Most attention was given to MGO, which was found to modify multiple proteins in cancer patients [105]. Interestingly, MGO was shown to have a dual effect on cancer cells. At high concentrations, it was shown to have an anti-cancer effect due to its cytotoxicity. This led to the development of various inhibitors of deglycases, which induce an increase in MGO levels and subsequent apoptosis in cancer cells. Moreover, given that knockout animals for key glyoxalase/deglycases are viable, targeting cancer cells’ dependence on these enzymes with small molecule inhibitors presents a new therapeutic avenue for treating cancer. Conversely, MGO-induced stress was shown to enhance tumor formation and progression at lower concentrations [105]. Therefore, small molecules, including penicillamine, aminoguanidine, and L-carnosine, have been used to scavenge MGO, decrease its levels in cancer cells, and abate tumor development [106–108].

Although much progress has been made in the field, we are only beginning to understand how NECMs on chromatin might serve as a link between metabolic stress and cancer progression (see Outstanding questions). We hypothesize that NECMs will expand the so-called “histone code” that has been implicated as a major regulator of cell fate and offer a new layer of epigenetic control. A better understanding of glycation patterns on histones, through the development of new analytical tools, will offer a new path for cancer diagnostics and therapeutics.

Outstanding Questions.

Are non-enzymatic modifications damage that needs to be repaired or do they represent a new family of histone modifications?

Are glycation adducts recognized by dedicated “reader” proteins that may lead to downstream effect on chromatin?

Are glycation adducts on histones a consequence of cancer or do they also contribute to oncogenesis?

Can we identify more erasers and if yes, what is their function in maintaining chromatin integrity?

What are the exact roles of MGO at various cellular concentrations in tumor progression?

How do glyoxal, ribose, and other reactive sugar species influence chromatin structure and function? Do they also play a role in tumor progression?

Is inhibiting glycation response factors and oncoproteins (GLO1/2, PAD4, FN3K, DJ-1) a viable therapeutic strategy for cancer treatment?

Highlights:

• Cancer cells undergo metabolic reprogramming to increase rates of glucose uptake and lactate secretion, leading to elevated levels of reactive sugars and metabolic by-products such as methylglyoxal (MGO).

• Cumulative evidence indicates that these reactive molecules can modify chromatin and particularly its main component, histones, in a process called glycation. Accumulation of glycation adducts on histones alters gene expression and thus cellular fate, in a similar mechanism to the well-known enzymatically introduced post-translational modifications (PTMs).

• Glycation adducts on histones and other proteins as well as glycation-induced responses are proposed to serve as early cancer markers to monitor abrogated cell metabolism.

• To counter glycation-induced cellular disturbance, defense systems to scavenge reactive sugars or reverse glycation adducts are upregulated in cancer. Inhibition of these response systems offers a new path for anti-tumor therapeutics.

Glossary

Advanced glycation end products (AGEs)

potentially harmful and heterogeneous products derived from a glycation chemical reaction cascade

Chromatin

a physiologically relevant complex of DNA and proteins that forms the chromosomes found in the nuclei of eukaryotic cells. The fundamental unit of chromatin is a nucleosome, which is composed of histones and DNA

Competitive inhibitors

inhibitors that resemble the normal substrate and bind to the enzyme’s active site when the substrate has not already bound to directly prevent the substrate from binding

Crosslinking

the process of forming a covalent bond between two molecules

Dicarbonyl

a highly reactive molecule containing two carbonyl groups that are known to react with proteins and DNA

Deglycase

an enzyme that removes glycation adducts from proteins and DNA

Epigenetics

the study of phenotypic changes caused by alterations in gene expression rather than in the DNA sequence

Glycation

the spontaneous non-enzymatic reaction of biological macromolecules with reducing sugars or aldehyde-containing sugar metabolites

Glycolysis

the metabolic pathway that converts glucose into pyruvate to release energy

Histones

the four core histones (H2A, H2B, H3, and H4) are the main component of chromatin and they consist of a highly basic N-terminal tail which is susceptible to enzymatic and non-enzymatic modifications

Maillard reaction

a chemical reaction between amino acids and reducing sugars that gives browned food its distinctive color and flavor

Methylglyoxal (MGO)

a reactive dicarbonyl species which is a by-product of glycolysis and is known to modify histones, changing their biological function

Mixed-type inhibitor

an inhibitor that binds to the enzyme at a location distinct from the substrate binding site, whether or not the enzyme has already bound the substrate

Multidrug resistance

the principal mechanism by which cancer cells develop resistance to multiple structurally and mechanistically unrelated chemotherapeutic drugs

Non-enzymatic covalent modifications (NECMs)

the covalent modifications on proteins and DNA formed by spontaneous reactions with small molecules in the body

Post-translational modifications (PTMs)

the covalent modifications of proteins following protein biosynthesis, known to regulate gene expression and cellular fate

Propionylation

the chemical reaction of propionyl groups to a lysine or arginine amino acid in order to protect them from trypsin cleavage in mass spectrometry sample preparation

Warburg effect

a distinctive form of cellular metabolism found in cancer cells whereby energy is produced predominantly through a less efficient process involving high level of glucose uptake and lactate secretion, even in the presence of oxygen (aerobic glycolysis)