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Аннотация научной статьи по фундаментальной медицине, автор научной работы — Kosianova Aleksandra, Tiasto Vladlena, Yatsunskaya Margarita, Khotimchenko Yuri, Kagansky Alexander

The etiology and pathogenesis of malignant tumor growth are associated with impaired gene expression, leading to accelerated proliferation, evasion of apoptosis, and metabolic deregulations with abnormal blood supply and innervation. Currently, hundreds of tumor suppressor genes and proto-oncogenes are known. Mutations, epigenetic alterations, exposure to viruses, and other environmental factors can cause pathological changes in gene expression. The key mechanisms of carcinogenesis are now considered to be linked to epigenetic events. A better understanding of epigenetic targets and pathways is needed to develop new strategies in antitumor chemotherapy. The majority of modern cancer drugs were taken from nature, yet only a small fraction of natural molecular diversity has been explored to date. Therefore, there is great interest in identifying new natural molecules for modulating gene expression by rewiring epigenetic pathways. This review is focused on examples of known natural molecules available to biomedicine, especially ones capable of modulating epigenetic landscapes and therefore relevant for cancer prevention and aging.

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Natural molecules as modulators of epigenetic silencing in human cells for cancer care and aging

Aleksandra Kosianova1, Vladlena Tiasto2, Margarita Yatsunskaya23, Yuri Khotimchenko1, and Alexander Kagansky2t

''Department of Pharmacy and Pharmacology, School of Biomedicine,

Far Eastern Federal University, 10, Ajax Bay, Russky Island, Vladivostok, 690922, Russian Federation

2Centre for Genomic and Regenerative Medicine, School of Biomedicine,

Far Eastern Federal University, 10, Ajax Bay, Russky Island, Vladivostok, 690922, Russian Federation

3Federal Scientific Center of the East Asia Terrestrial Biodiversity, Far East Branch of

the Russian Academy of Sciences, pr. 100-letiya Vladivostoka, 159, Vladivostok,

690022, Russian Federation

Address correspondence and requests for materials to Aleksandra Kosianova, kosjanova_aleksandra@icloud.com


Citation: Kosianova, A., Tiasto, V., Yatsunskaya, M., Khotimchenko, Yu., and Kagansky, A.+ 2020. Natural molecules as modulators of epigenetic silencing in human cells for cancer care and aging. Bio. Comm. 65(4): 315-330. https://doi. org/10.21638/spbu03.2020.405

Authors' information: Aleksandra Kosianova, Assistant, orcid.org/0000-0001-5655-5855; Vladlena Tiasto, PhD Student, orcid.org/0000-0001-6030-2543; Margarita Yatsunskaya, Researcher, orcid.org/0000-0002-4718-6186; Yuri Khotimchenko, Dr. of Sci. in Biology, Professor, orcid.org/0000-0002-6979-1934; Alexander Kaganskyf, orcid.org/0000-0002-6219-6892

Manuscript Editor: Alla Krasikova, Department of Cytology and Histology, Faculty of Biology, Saint Petersburg State University, Saint Petersburg, Russia

Received: January 26, 2020;

Revised: May 5, 2020;

Accepted: July 15, 2020.

Copyright: © 2020 Kosianova et al. This is an open-access article distributed under the terms of the License Agreement with Saint Petersburg State University, which permits to the authors unrestricted distribution, and self-archiving free of charge.

Funding: This work was supported by the Russian Science Foundation (Project No. 20-15-00378).

Competing interests: The authors have declared that no competing interests exist.

The etiology and pathogenesis of malignant tumor growth are associated with impaired gene expression, leading to accelerated proliferation, evasion of apoptosis, and metabolic deregulations with abnormal blood supply and innervation. Currently, hundreds of tumor suppressor genes and proto-oncogenes are known. Mutations, epigenetic alterations, exposure to viruses, and other environmental factors can cause pathological changes in gene expression. The key mechanisms of carcinogenesis are now considered to be linked to epigenetic events. A better understanding of epigenetic targets and pathways is needed to develop new strategies in antitumor chemotherapy. The majority of modern cancer drugs were taken from nature, yet only a small fraction of natural molecular diversity has been explored to date. Therefore, there is great interest in identifying new natural molecules for modulating gene expression by rewiring epigenetic pathways. This review is focused on examples of known natural molecules available to biomedicine, especially ones capable of modulating epigenetic landscapes and therefore relevant for cancer prevention and aging. Keywords: cancer, aging, natural products, silencing, methylation, histone modification, signaling pathways

Epigenetic regulation and chromatin

Epigenetic processes include changes in gene expression that happen irrespectively of alterations in DNA sequences (Schubert et al., 2015). The outcomes may have contrasting functional consequences depending on the structural organization of chromatin. For example, "open chromatin", called euchromatin, promotes gene expression, while heterochromatin ("closed chromatin") suppresses it (Sutherland et al., 2003). Furthermore, heterochromatin is involved in processes of dosage compensation, allelic imprinting, cell- and tissue-specific gene expression, and many other aspects of molecular cell biology, which are being actively researched in the last few decades. Substantial heterochromatin domains span arrays of hundreds and thousands of repeated elements as integral elements of functional centromeres in most eukaryotes (Buscaino et al., 2010). As a rule, these heterochromatic regions in most genomes lack active genes, and the transcription of genes located in the heterochromatin is inhibited because the resident DNA sequences attract chromatin-modifying activities that counteract functional assembly of the transcription machinery (Huisinga et al., 2006; Grewal et al., 2007). However, while the formation of heterochromatin on repetitive elements makes these regions transcriptionally inert, it promotes genome stability by regulating

recombination, DNA repair, and chromosome segregation (Grewal et al., 2007). Recent experiments have made it possible to model gene expression, taking into account many factors, including nucleosome dynamics and binding of activators and repressors (Teif et al., 2011). Moreover, loss of gene expression, called epigene-tic gene silencing, is one of the most frequently observed mechanisms exploited by cancer in order to modulate cell fates (Urnov et al., 2001).

DNA methylation is the most widely studied epigen-etic mark, and it plays important roles in regulating gene expression and maintaining genome stability in a spectrum of species including plants, rodents, and humans (Weber et al., 2007; Qian et al., 2014; Xu et al., 2015). DNA methylation in general is defined as a biochemical process whereby a methyl group is added to DNA bases. It usually occurs on the fifth position of cytosine (C) to form 5-methyl cytosine, known as 5mC in the context of CpG dinucleotides — regions of DNA where a cytosine is followed by a guanine along the 5'^3' direction in both eukaryotes and prokaryotes (Weber et al., 2007; Qian et al., 2014; Xu et al., 2015).

The effect of 5mC is traditionally considered to interfere with transcriptional initiation, which thereby silences gene expression (Jones et al., 1999).

Posttranslational modifications of proteins are one of the main determinants of genomic functions, providing a fast, controlled and reversible response to environmental signals (Khoury et al., 2011). Such modifications can be caused by phosphorylation, nitrosylation, methylation, ubiquitylation, sumoylation, and other chemical reactions, with the most well studied ones being acetyla-tion and methylation (Choudhary et al., 2014). Adding acetyl groups to the lysine residues in the protein is catalyzed by lysine acetyl transferases changing the charge and structure of the molecule, leading to a change in its function (Azevedo et al., 2016). In the last two decades, the acetylation of histone molecules (by histone acetyl transferases, HATs) was attracting particular interest and has been shown to be involved in the complex combinatorial regulation of local genome properties such as transcription, DNA repair and other chromosomal transactions. Histone deacetylases (HDACs) comprise a class of enzymes, reversing acetylations, responsible for epigenetic regulation of gene expression and playing critical roles in cellular processes including cell proliferation, apoptosis, differentiation, and angiogenesis. Methylation of histones can be either repressive in relation to transcription — such as methylation of histone H3 lysine-9 methylation (H3K9me), which dominates heterochromatic areas — or transcription-promoting (e.g., H3K4me) (Rea et al., 2000; Jenuwein et al., 2001). Methylation of H3K9 allows binding of specific chromodomain proteins, including HP1 (heterochromatin protein 1) variant, which interact with various key chro-

Table 1. Some of the posttranslational modifications and "Histone code" model for acetylation and methylation in various locations (Kim et al., 2014)












Amino acid and its position





























Some of the factors involved



MLL4, Gcn5, KAT5/Tip60


SUV39h1/h2, G9a



EZH2, G9a


DOT1L/S.c. Dot1




KAT5/Tip60, Hat1,

Hat1, Esa1


Gcn5, Esa1




Gcn5, KAT5/Tip60


p300, CBP/Gcn5


Hat1, Tip60

Gcn5, PCAF, Tip60

Hat1, Esa1

Gcn5, KAT5/Tip60

matin modifying activities (Bannister et al., 2001; Na-kayama et al., 2001). Table 1 gives a list of modifications, mostly acetylation and methylation, that sometimes are referred to as a histone code.

Of the many diseases that can be associated with epigenetic deregulations, the most common and widely studied are cancers. Cancer can occur due to the activation of oncogenes and/or repression of tumor suppressors. Numerous clinical and experimental data suggest that tumor cells generally exhibit genome-wide hypo-methylation and localized hypermethylation, compared

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Table 2. HDAC inhibitor mediated biological effects

(Abbreviations: BCL, B-cell lymphoma; CDK, cyclin dependent kinase; CXCR4, chemokine (C-X-C motif) receptor 4; DSB, double strand breaks; FLIP, flice inhibitory protein; HIF, hypoxia inducible factor; IAP2, inhibitor of apoptosis; ICAM1, intercellular adhesion molecule 1; IFN c, interferon c; IL-1, interleukin 1; MCL 1, myeloid cell leukemia sequence 1; MHC, major histocompatibility complex; NF-jB, nuclear factor — jB; PP1, protein phosphatase 1; pRb, retinoblastoma protein; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TNF a, tumor necrosis factor a; TrX, thioredoxin; TBP2, TrX binding protein 2; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; uPA, urokinase plasminogen activator; XIAP, X-linked inhibitor of apoptosis.) (According to data from Manal et al., 2016)

Biological effects of HDAC inhibitors Mechanisms of their implementation

Cell cycle arrest at G1/S or G2/M/phases Induction of CDKN1A to encode p21waf1/CIP1 promoting pRb hypo-phosphorylation

Repression of genes, Cyclin D and Cyclin A, to reduce CDK2 and CDK4 kinase activities and hypophosphorylation of pRb

Induction of p27 which inhibits CDK2- and CDK4-containing complexes

Repression of genes for DNA synthesis, CTP synthase and thymidylate synthetase

Activation of G2-phase checkpoint through heterochromatin hyperacetylation leads to abnormal chromosomal segregation and fragmentation of nucleus

Oxidative stress and DNA damage Accumulation of ROS in tumor cells to induce mitochondrial disruption

Downregulation of TrX (scavenger of ROS)

Indirect DNA damage by increased accumulation of phosphorylated histone variant, cH2AX (marker of DSB in DNA)

Repression of genes for DNA repair proteins, RAD51, BRAC1, BRCA2, Ku70 and Ku86

External pathway of mediated apoptosis Upregulation of TRAIL, DR5, Fas, Fas-L and TNFain transformed tumor cells; thus activation of Casp 8 and 10

Repression of genes encoding for DR inhibitors, FLIP and IAP2

Mitochondrial pathway of mediated apoptosis Upregulating expression of pro-apoptotic (anti-survival) proteins of BCL2 family, namely Bid, Bim, Bmf

Downregulation of expression of anti-apoptotic (pro-survival) BCL2 family proteins (BCL2, BCL-XL, BCL-w), MCL-1 and XIAP

Gene induction for encoding mediators causing mitochondrial damage (Diablo, Casp 9, Apafl, Cyt C and Htr A2)

Autophagy and aging Overexpression of BCL-XL thereby inducing autophagy-mediated cell death

Aging through polyploidy and withdrawal of cell cycle

Anti-angiogenesis Repression of pro-angiogenesis factors, HIF-1a, VEGF and CXCR4

Upregulation of tumor suppressor VHL protein and p53

Immunomodulation Augmenting tumor cell antigenicity by upregulating MHC class I and II proteins, costimulatory molecules (CD40, CD80 and CD86) and ICAM1

Inducing expression of MHC class I chain-related molecules, MICA and MICB

Suppression in secretion of pro-inflammatory cytokines, TNF a, IL-1 and IFNc

Non-histone substrate mediated Hyperacetylation of transcription factors, E2F1, p53, STAT1, STAT3 and NF-jB

Hyperacetylation of proteins, Hsp90, a-tubulin, to induce protein degradation, cell growth inhibition, cell death

Disruption of HDAC-PP1 complexes and activation of PP1 to cause irregularity in tumor cell phosphorylation and acetylation

Disruption of aggresome pathway for degradation of misfolded protein aggregates

to normal cells. Interactions between DNMTs and his-tone methyltransferases, such as EZH2 and SETD2, play critical roles in epigenetic disruption during malignancy (Wu Zhang et al., 2017). Mechanisms by which overexpression of histone demethylase LSD1 leads or contributes to tumor formation could involve its capacity to silence tumor suppressor genes as a transcriptional co-

repressor, mainly through H3K4 demethylation. In addition, non-coding RNAs, e.g., micro-RNAs (miRNAs), and long non-coding RNAs (lncRNAs) were the focus of attention in terms of epigenetic control. With the development of RNA sequencing methodologies, a number of such non-coding RNAs were identified and characterized (Hassan et al., 2015). In addition, new evidence

has complicated the paradigm of epigenetic landscapes, suggesting the role of lipids in gene regulation (Zhdanov et al., 2015), as well as the discovery of chromatin factors involved in both repression and activation. For example, H3.3, a histone variant of H3, is commonly associated with transcription activation (Ahmad et al., 2002).

Unlike genetic mutations, epigenetic changes can be reversible. This reversibility led to the emergence of the concept of "epigenetic therapy", according to which the reactivation of epigenetically silent tumor suppressor genes can restore growth control in cancer cells (Jones et al., 2007; Marks 2010; Santos et al., 2010; Taby et al., 2010). As noted earlier, histone acetylation and deacetylation are catalyzed by specialized enzymes, namely histone (lysine) acetyltransferases (HATs/KATs) and HDACs, which affect specific tissues and genomic contexts differently (Chen et al., 2015; Venkatasubramani et al., 2015). It has long been established that many cancers are characterized by global hypoacetylation of histones (Fraga et al., 2005). Overexpression of individual HDACs is associated with reduced survival rates in numerous tumors, including colon, breast, lung and prostate cancer (West et al., 2014). In addition, the genetic knockdown of specific HDACs in these tumors caused cell cycle arrest and apoptosis.

Multiple biological effects of HDAC inhibitors are presented in Table 2.

As a result, numerous HDAC inhibitors have been clinically tested, and some have recently been approved by the FDA for use in various forms of human cancer (Ma et al., 2016). It is hoped that these HDAC inhibitors can be used in tumors that have developed resistance to conventional treatments or after a relapse of primary cancer (Bo-jang et al., 2014). It has been clearly demonstrated that the patterns of global acetylation of H3 and H4 correlate with the severity of prostate and other cancers, (Seligson et al., 2005) while global methylation patterns may have diagnostic and prognostic potential for a number of different tumors (Lizcano et al., 2012). Recently, the main efforts of epigenetic therapy were aimed to develop and refine inhibitors of two families of HDACs and DNMTs (Jones et al., 2007; Taby et al., 2010; Li-Ting Wang et al., 2014).

Natural modulators of cellular pathways

Natural compounds are a key source of drugs in modern biomedicine (Neergheen-Bhujun et al., 2017). Various types of natural molecules inhibiting silencing can be considered a fruitful avenue both for chemotherapy of cancers and for aging control. In the first part of our review we extensively cover the existing literature and perspectives concerning these types of molecules. In the second part we summarize other potentially interesting enzymes and their inhibitors that may join the therapeutic repertoire in the future. Recently it has been proved that natural compounds such as curcumin, epigallo-

catechin gallate and resveratrol could alter epigenetic mechanisms which can lead to increased sensitivity of cancer cells to conventional agents and thus inhibit tumor growth (Li et al., 2010). A number of studies have reported on curcumin effects on HDAC expression. It is known that curcumin is also a potent HDAC inhibitor, which is more effective than valproic acid and sodium butyrate (Bora-Tatar et al., 2009). Another study has reported that levels of HDAC 1, 3, and 8 were significantly reduced by curcumin, leading to increased levels of acetylated histone H4 (Liu et al., 2005). Similarly, a significant reduction in HDAC1 and HDAC3 was observed upon treatment with curcumin (Chen et al., 2007).

Currently, more than 60 % of the FDA-approved anticancer drugs are derived from natural compounds isolated from various types of organisms (Neergheen-Bhujun et al., 2017). These include plants (e.g., vincristine, vinblas-tine, etoposide, paclitaxel, camptothecin, topotecan, and irinotecan), marine organisms (e.g., cytarabine, aplidine, and dolastatin), and microorganisms (e.g., dactinomycin, bleomycin, and doxorubicin). A number of natural compounds relevant to cancer prevention and/or therapy have been derived from fruits and vegetables. These include: curcumin (from turmeric), resveratrol (from red grapes, peanuts, and berries), genistein (from soy), diallylsulfide, S-allylcysteine and allicin (from garlic), lycopene (from tomatoes), capsaicin (from chili peppers), diosgenin (from fenugreek), 6-gingerol (from ginger), ellagic acid (from pomegranates), ursolic acid (from apples, pears, prunes, etc), silymarin (from milk thistle), anetol (from anise, camphor, or dill), catechins and Epigallocatechin gallate (EGCG) (from green tea), eugenol (from cloves), indole-3-carbinol (from cruciferous waxes), and many others (Bhanot et al., 2011; Pratheeshkumar et al., 2012; Craig et al., 2013; Wai-Leng et al., 2013; Bailon-Moscoso et al., 2017). It has been shown that these natural compounds may change localized and global gene expression, induce apoptosis, or affect the activity of ligand-depen-dent receptor activators and oxidative stress modulators, leading to cell cycle shutdown, necrosis, and autophagy (Kong et al., 2012; Pratheeshkumar et al., 2012; Shukla et al., 2014). A number of studies have shown that cur-cumin, EGCG, resveratrol, sulforaphane, Gallic acid, genistein, 3,3'-diindolylmethane, and other natural molecules alter epigenetic processes, including DNA meth-ylation, histone modification, chromatin remodeling, microRNA regulation, and thereby, cell fates. Examples of identified protein targets of such molecules include the activator Protein 1 (AP-1), Inhibitor of Differentiation

4 (ID4), Nuclear Factor-kappaB (NF-kB)/REL-A, Signal Transducer and Activator of Transcription (STAT)-3,

5 and 6, MYC, Runt-related transcription factor (RUNX)-1, NOTCH 1-4, CCAAT/Enhancer Binding Protein alpha (C/EBPa), p-catenin (CTNNB1), Sterol Regulatory Element-Binding Protein (SREBP)-1c, members of Tu-

Inhibition of several kinases involved in the signal transduction

Suppressing the proliferation, differentiation, metastasis and angiogenesis of cancer cells

MicroRNAs (miRNAs) caspases

B cell lymphoma 2 (Bcl-2) family proteins

Nuclear factor (NF)-Kb

Epidermal growth factor (EGF) / epidermal growth factor receptor (EGFR)

Phosphatidylinositol-3-kinase (PI3K) / Akt

Mitogen-activated protein kinase (MARK)

Fig. 1. The signaling pathways of polyphenols in cancer.

mor Protein (TP)-p53 family Interferon Regulatory Factor (IRF)-5, SMAD4, GLI factors, Krüppel-Like Factor (KLF)-5, MIcrophthalmia-associated Transcription Factor (MITF), PAX family members, TWIST, and Wilms' Tumor factor 1 (Lee, 2007; Kikuno et al., 2008; Andreoli et al., 2010; Lee et al., 2010; Tuntiwechapikul et al., 2010; Chen et al., 2011; Fujiwara Komohara et al., 2011; Li et al., 2011; Lee et al., 2013;).

Alkaloids and polyphenols are the predominant molecules in use for the treatment of cancer. Many natural polyphenols have cytostatic and apoptotic properties due to their antioxidant characteristics. Anti-carcinogenic activity of polyphenols includes suppression of proliferation, differentiation, metastasis, and angiogenesis of various types of cancer cells through inhibition of several kinases involved in signal transduction. Polyphenols can easily bind and cross cell membranes and interfere with various molecular mechanisms in the cell, including caspases, B cell lymphoma 2 (Bcl-2) family proteins, nuclear factor (NF)-kB, epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK) (Li-rui Sun et al., 2019) (Fig. 1).

We will next discuss some of the natural compounds and their targets in detail.

Curcumin, EGCG, and Reservatrol and epigenetic regulation

Curcumin (diferuloylmethane), a polyphenol from Curcuma longa, inhibits tumor cell growth and induces tumor cell death. Moreover, curcumin could modulate various signaling pathways involved with inflammation,

proliferation, invasion, survival, and apoptosis (Huang et al., 1997; Teiten et al., 2010). It has been shown that curcumin induces p63 and MYC-associated factor X (MAX), and also inhibits NF-kB in hepatocarcinoma cells and OCT4 in pluripotent cells of embryonal carcinoma of the placenta (NCCIT). Some scientists suggest that these genes could act as potential therapeutic targets, especially in cancer stem cells. (Zang et al., .2014; Marquardt et al., 2015). Recent studies have found that curcumin lowers the activity of NF-kB and NOTCH1 in human hematopoietic Raji cells by inhibiting the interaction of histone deacetylases (e.g., HDAC1, HDAC3) with E1A-binding protein 300 (EP300) and their binding with cAMP response element. Also, cur-cumin could modulate the expression of transcription factor components AP-1, c-FOS, and c-JUN (Muk-hopadhyay et al., 2001; Park et al., 2005; Prusty et al., 2005; Chen et al., 2007; Lin et al., .2007). Curcumin had caused DNA damage and led to apoptosis in p73 and p53-deficient human hepatoma cells Hep3B (Wang et al., .2015). It was found that curcumin induces global and sequence-specific demethylation of the epigeneti-cally silenced genes in human leukemia cells (Liu et al., 2009). Consistent with this, an in silico study has shown that curcumin could covalently block the catalytic thiol group in the C1226 DNMT1 binding site (Medina-Franco et al., 2011).

Tea polyphenols isolated from green tea Camellia sinensis include epicatechin, epicatechin-3-gallate (EGCG), epigallocatechin and epigallocatechin-3-gal-late. Epicatechin gallate induced tumor cell death by activating TP53 and stimulating mitogen-activated protein kinase p38 (MAPK) and c-Jun N-terminal kinases

(JNK) in human colon cancer cells in vitro (Cordero-Herrera et al., 2013). The main polyphenols in black tea are: catechins, flavonoids, methylxanthines, theaflavins, and thearubigins (Siddiqui et al., 2006). The compound Polyphenon-B, isolated from black tea, suppressed the growth of hepatocellular carcinomas in rats (induced by 3,3'-diaminobenzidine), while simultaneously reducing the expression of hypoxia-induced factor (HIF) -1a and increasing HDAC1 levels (Murugan et al., 2009). Several studies have reported the inhibitory effects of tea polyphenols on DNA methylation in ovarian, oral, esopha-geal, breast, stomach, prostate, skin, colorectal, pancreatic and head and neck cancers. (Fang et al., 2007; Dou, 2009; Link et al., 2010; Pandey et al., 2010; Ho E. et al., 2011; Henning et al., 2012, 2013; Gerhauser, 2013; Saha et al., 2013).

Recent structural and molecular modeling studies have shown that the structures of D — and B-cycles of tea polyphenols (EGCG, for example) inhibit the DN-MTs activity (Lee et al., 2005). It has been shown that EGCG bind Pro-1223, Glu-1265, Cys-1225, Ser-1229, and Arg-1309 in the catalytic pocket of DNMT1 protein. (Lee et al., 2005; Thakur et al., 2014). Catechol-containing polyphenols inhibit DNMTs by increasing the o-methylation of SAM by the enzyme catechol-O-methyltransferase, direct inhibition of the enzyme di-hydrofolate reductase activity, disruption of the folate cycle and increased SAM levels, and direct inhibition of DNMTs [Lee et al., 2005; Thakur et al., 2014). It has been reported that EGCG reverse hypermethylation of Cdkn2a, retinoic acid receptor-^ (RarE), O-6-methyl-guanine-DNA-methyltransferase (MGMT), and MutL Homolog-1 (MLH1) genes by inhibiting DNMT1 activity in human esophageal cancer KY55 cells by binding to the DNMT1 catalytic pocket and by inhibiting its enzyme activity (Lu et al., 2007; Xiao et al., 2007; Gao et al., 2009). Also, EGCG inhibits DNMTs activity and reactivate the RarE gene suppressed by methylation in human colon and prostate cancer cells (Lee et al., 2005). EGCG could demethylate the promoter regions of DNA of genes encoding annexin A1 (ANXA1) and inhibit Wnt1(WIF1) factor in lung cancer cells (Lu et al., 2007; Xiao et al., 2007; Gao et al., 2009). Exposure of human epidermoid carcinoma A431 cells to EGCG decreased global levels of DNA methylation and activity and DNMT proteins DNMT1, DNMT3A, and DNMT3B (Nandakumar et al., 2011). At the same time, it was discovered that EGCG reactivated silenced CDKN1A and CDKN2A (Nandakumar et al., 2011). Effects of green tea-derived EGCG have been demonstrated in cancer cells of the esophagus, oral cavity, skin, lungs, breast, and prostate cancer models (Henning et al., 2013). Transcription factors (e.g., NF-kB, AP-1, CREB, and HIF-1a) were suppressed in mouse melanoma cells when treated with a combination of EGCG with dacarbazine or quer-

cetin with sulforaphane (Liu et al., 2001; Pradhan et al., 2010; AlQathama et al., 2015; Feitelson et al., 2015).

Resveratrol [3, 5, 4'-trihydroxy-trans-stilbene] is a natural polyphenol from blueberries, mulberries, cranberries, peanuts, and grapes. It was shown that resvera-trol has a pronounced anticancer potential. Resveratrol inhibits the transmission of Hif1a-mediated androgen receptor signals and reduces the proliferation of prostate cancer cells in vitro and tumor progression in vivo (Mi-tani et al., 2014). A recent study showed that resveratrol works to inhibit the development of pancreatic cancer in KRAS mutant mice (Shankar et al., 2011). It has been further discovered that resveratrol induces apoptosis in human cancer stem cells, activating caspase-3/7 and inhibiting the expression of BCL-2 and XIAP proteins (Shankar et al., 2011; Wang et al., 2013). Resveratrol inhibits the expression of metastasis associated pro-tein-1 (MTA1), a known component of the nucleosome remodeling and deacetylation complex NuRD, which is overexpressed in some cancer types, including prostate cancer (Kai et al., 2010; Dhar et al., 2015; Levenson et al., 2015). As a result of MTA1 expression inhibition, resveratrol interfered with MTA1 / HDAC1 interaction in the NuRD co-repressor complex, causing increased TP53 expression and acetylation, which subsequently led to an increase in Bax and p21 expression, leading to apoptosis in prostate cancer cells (Kai et al., 2010; Levenson et al., 2014; Dhar et al., 2015). Pterostilbene found in blueberries, a natural resveratrol derivative, has also been found to greatly increase the MTA1-me-diated TP53 acetylation (Li et al., 2013). Resveratrol and pterostilbene were also found to suppress tumor growth, progression, local invasion, and spontaneous metastases in orthotopic prostate cancer xenografts in another study (Li et al., 2013). Resveratrol inhibited HDAC1, HDAC2, MTA1, MTA2, and MTA3 proteins of NuRD complex in prostate cancer DU145 cells and activated the PTEN tumor suppressor by increasing its acetyla-tion, which led to the inhibition of the AKT signaling pathway in prostate cancer (Levenson et al., 2014; Dhar et al., 2015). It has been further shown that resvera-trol induces autophagy by activating NAD-dependent deacetylase, SIRT1 (Cherblanc et al., 2013). However, other phenolic compounds found in red wine, including anthocyanins (ENIN), stilbenoid (piceatannol), phenols (gallic acid), glycosides (delphinidin, kuronen, peonidin), and flavonoids (catechin, epicatechin, quer-cetin, myrinet) were also shown to promote autophagy (Pietrocola et al., 2012). Resveratrol is selective for the class III HDACs such as SIRT1, SIRT2, SIRT3, as well as for the HAT, EP300 (Pietrocola et al., 2012). Also, resve-ratrol could induce prostate cancer cell death in vitro by the modulation of global gene expression rates through deacetylation of FOXO transcription factor in human pancreatic and prostate cancer cells in vitro and in vivo

Table 3. Effects of natural compounds on epigenetic and antitumor activity

Natural compounds Source Epigenetic/cellular effect Anticancer effect

Polyphenols: Resveratrol Grapes, peanuts DNMT 3b inhibitor; decrease in RASSF-1a methylation with increasing circulating resveratrol; Suppress expression of the androgen receptor Decreased risk of prostate cancer and breast cancer

Polyphenols: Genistein Soybeans Suppress expression of the androgen receptor (ER-P); inhibition of DMNT; demethylation of RARp, p16 and MGMT promoters; demethylation of promoters of miR-29a and miR-1256 Inhibition of prostate cancer cell proliferation and invasion; decreased risk of prostate cancer and breast cancer

Polyphenols: Epigallocatechin- 3-gallate Green tea Demethylation and/or suppressed methylation of TSG promoters (p15 and p16); inhibits HDAC activity. Antioxidant activity; inhibition of angiogenesis; induction of apoptosis; inhibited invasive metastasis in a human pancreatic adenocarcinoma cell line

Isothiocyanates Cruciferous vegetables Interaction with xenobiotic compounds, smoking and consumption of cruciferous vegetables Anti-cancer effect: induced apoptosis and suppressed metastatic potential in lung cells.

Folate Periconceptional folic acid supplementation; dark green leafy vegetables Higher IGF2 methylation in offspring; higher hMLH1 promoter methylation Lower birth weight; association with colorectal cancer risk

a linoleic acid Flaxseed Decreased expression of COX 1 and COX 2 when fed to male Fischer rats; Decreased COX 2 expression when fed to hens; Changed expression of genes associated with brain Tumor incidence, multiplicity and size decreased; reduction in ovarian cancer incidence and severity; influence on brain development

Trans fatty acids Industrially processed foods and low levels in meat DNA hypomethylation in the brains of offspring; histone modifications; hypomethylation at the SacII site in the ER gene in response to a diet high in omega 6 PUFA During seven years of follow-up serum trans MUFA levels were associated with risk of invasive breast cancer

(Chen et al., 2010; Ganapathy et al., 2010; Roy et al., 2011). Stemness transcription factors, namely NANOG, SOX2, c-MYC, and OCT4, were also inhibited by resve-ratrol, curcumin, and epigallocatechin-3-gallate in human cancer stem cells (Shankar et al., 2011; Ding et al., 2013; Wang et al., 2013; Yoon et al., 2014).

Effects of natural compounds on epigenetic and antitumor activity are shown in Table 3.

Rapamycin, metformin, and aging

For a long time, aging was considered an unforgiving road to decline and disease, but more recently, with the advancement of molecular and cellular insight into biology of the related processes, it is becoming evident that aging is plastic. Such plasticity could be used to approach aging of an organism and age-related diseases from a new perspective. In particular, aging is associated with deep epigenetic changes leading to changes in gene expression and disturbances in the broad genome architecture and epigenomic landscape. Although many studies have focused on genes involved in aging and the related diseases, the non-genetic regulation of aging is attracting increasing attention. The potential reversibility of these epigenetic changes, which occur as a sign of aging, offers exciting opportunities to change the trajectory of age-re-

lated diseases. Metformin and rapamycin are two FDA-approved mTOR inhibitors exhibiting significant anticancer and antiaging properties beyond their current clinical use. However, each one faces problems with approval due to side effects. These two drugs are also discussed in the context of caloric restriction as mimetics (Ingram et al., 2004). Caloric restriction is a well-known intervention to increase longevity in various species (Mattison et al., 2017), but it may have limited practical value to humans (Phelan et al., 2005). Caloric restriction mimetics will theoretically have their beneficial effects without actually reducing calorie intake. The hallmarks of calorie restriction are reduced circulating glucose and insulin levels, as well as responses to these reductions in nutrition and energy-sensitive networks, such as activation of AMP-activated protein kinase (AMPK) and inhibition of mammalian rapamycin target (mTOR) (Zhavoronkov, 2015). The mTOR pathway is particularly important, being essential for early development, but also potentially damaging in later years if not suppressed, contributing to cellular aging and disease (Blagosklonny, 2015). Inhibition of the mTOR pathway slows conversion to aging (Blagosklonny, 2015) and prolongs life expectancy in different species (Fabrizio et al., 2001; Vellai et al., 2003; Jia et al., 2004). Rapamycin and metformin, although different in clinical application, are both mTOR inhibitors and have multiple

anti-aging, anti-cancer, and cardiovascular benefits (Roth et al., 2016). Rapamycin (sirolimus) is an immunosuppressant used after kidney transplantation. It has been shown to reduce the risk of cancer after surgery in kidney transplant patients (Campistol et al., 2006; Yakupoglu et al., 2006; Garrick, 2007). Although the extent to which rapamycin's anti-cancer properties underlie its anti-aging action and/or vice versa remains a matter of debate (Bla-gosklonny 2015; Leontieva et al., 2015), it has also been reported or theorized to protect against a number of other aging-related diseases in humans with cardiovascular disease, osteoporosis, obesity, autoimmune diseases and arthritis, macular degeneration, diabetes, Alzheimer's disease and Parkinson's disease. While rapamycin interacts with various pathways associated with the transmission of nutritional signals, it acts primarily through direct interaction of the mTOR 1 complex (mTORCl) (Roth et al., 2016; Blagosklonny, 2017).

Through a combination of AMPK-dependent and -independent mechanisms (Zhou et al., 2001), metformin affects a number of signaling pathways, including IGF-1 (Lib et al., 2011), Sirtuin 1 (SIRT1) (Arunacha-lam et al., 2014; Zhong et al., 2015), and mTOR complex 1 (mTORC1) (Howell et al., 2017), which contribute directly or indirectly to its clinical response and multiple antitumor effects. Taken together, rapamycin and met-formin are promising candidates for increased longevity and health; however, concerns about side effects prevent their widespread use for this purpose. Although short-term use of rapamycin is considered safe, side effects such as wound complications, oral ulcers, diarrhea, hy-pokalemia, bronchopneumonia, proteinuria and withdrawal syndrome are possible.

Metformin, although relatively safe, is poorly tolerated in one quarter to half of patients due to gastrointestinal side effects (Dujic et al., 2016). Given the urgent need for the prevention of aging and the prevention of diseases associated with it, it would be useful to consider natural alternatives such as nutraceuticals that would be safe enough for widespread use (Nasri et al., 2014).

The central question is whether epigenetic drugs will solve the problem of age-related diseases that accumulate in the elderly. Thus, it will be worthwhile to test epigenetic drugs for several age-related diseases (Brunet et al., 2014).

Other natural small molecules and cancer epigenetics

Other natural molecules have striking effects relevant for cancer research. For example, sulforaphane induces anticancer activity and enhances xenobiotics metabolism, causing cell cycle arrest and apoptosis in human cancer cells (Clarke et al., 2008). Sulforaphane reduced the enzymatic activity of DNMT1 and DNMT3A and demethyl-

ated the first exon of the human TERT gene in human colon cancer cells and in breast cancer cells (Traka et al., 2005; Meeran et al., 2010). It was found that sulforaphane and 3,3'-diindolylmethane induced the reactivation of tumor suppressor genes suppressed in cancer cells by DNA methylation (Kaufman-Szymczyk et al., 2015). Also, it has been shown that both sulforaphane and 3,3'-diindolyl-methane could reduce the expression of DNA methyl-transferases, leading to general hypomethylation of promoters in androgen-dependent and -independent human prostate cancer cells (Wong et al., 2014). Interestingly, sulforaphane and 3,3'-diindolylmethane have common gene targets that are actively involved in the progression of the same type of cancer (Wong et al., 2014). Phenethy-lisothiocyanate was found to inhibit growth and induce apoptosis in cancer cells (Cheung et al., 2010). Human prostate cancer cells exposed to phenethylisothiocyanate demonstrated demethylation of the GSTP1 gene promoter, reduced HDAC activity and activated acetylation and methylation of histones at specific loci (Wang et al., 2007). Indole-3-carbinol is purified from the representatives of the cruciferous family (Brassicaceae), including broccoli, cabbage, cauliflower, mustard, and radish. In the acidic environment of the stomach, indole-3-carbinol is converted into diindolylmethane. Both indole-3-carbinol and diindolylmethane induced apoptosis in various cancer cell lines by modulation of nuclear receptor mediated signals (Rahman et al., 2006; Banerjee et al., 2011; Chen et al., 2012; Safa et al., 2015). Indole-3-carbinol inhibits NF-kB activity and stimulates the p53-dependent pathway and its downstream target genes and activates apop-totic protease factor (APAF) -1 in acute lymphoblastic leukemia cells (MDA-MB-231 and MCF-7) by suppressing STAT3 and NF-kB signaling (Chung et al., 2015). Ku-kurbitatsin B from Hemsleya endecaphylla reduced tumor cell proliferation and induced their apoptosis through modulating the STAT3 pathway in the human lung cancer cell line (Zhang et al., 2014). It has been reported that a compound from Eurycoma longifolia, eurycomanone, inhibited the viability and proliferation of Jurkat and K562 cells but didn't have such an effect on benign cells (Orlikova et al., 2013; Hajjouli et al., 2014). Strikingly, eurycomanone repressed the NF-KB signaling by inhibiting IkB phosphorylation and signaling by the mitogen-activated protein kinase (Orlikova et al., 2013; Hajjouli et al., 2014). Aaptamine from the marine sponge Aaptos sp. was shown to reduce the proliferation of various human cancer cell types by modulating AP-1, NF-kB, and p53-dependent transcription activity (Dyshlovoy et al., 2014). Codenomicon, a sesquiterpene lactone from Chloranthus henryi, inhibits cancer cell invasion, migration, and metastasis of breast cancer cells, inhibiting RUNX2 tran-scriptional activity (Wang W et al., 2014). Kirstin from Uncaria rhynchophylla is an anti-metastatic phytochemi-cal that inhibits the invasion of breast cancer cells through

targeting of NF-kB factor for activation (Lou et al., 2014). Bergamottin is a natural furanocoumarin from grapefruit juice that promotes the apoptosis of myeloma cells via inhibiting the STAT3 signaling (Kim et al., 2014). Annona muricata extract induced cell cycle arrest and apoptosis in A549 cells by activating mitochondrial mediated signaling and suppressing nuclear translocation of NF-kB (Moghadamtousi et al., 2014).

Ethanol extracts of Piriformospora indica roots significantly increased the expression of TP53 protein in human nasopharyngeal carcinoma cells in a time- and dose-dependent manner (Kao et al., 2015). It has been further shown that grifolin from Albatrellus confluens fungus induced cell cycle arrest in various human cancer cells by targeting extracellular signal-regulated kinase 1 or by activating the death-associated protein kinase (DAPK) -1 via regulating TP53 transcription (Luo et al., 2015). Chalcons are natural compounds from various spices, tea, beers, fruits and vegetables, which can modulate transcription factors employed by key cancer pathways, including TP53, NF-KB, STAT3, AP-1, NRF2, and Wnt (Jandial et al., 2014). It was found that the herbal alkaloid carbazole mahanine activates TP53 protein, which leads to the accumulation of reactive oxygen species in the nucleus. It also affects PTEN and its interaction with TP53 / TP73 proteins in colorectal cancer cells, and it was also shown to inhibit STAT3 expression in cervical cancer cells (Das et al., 2014).

Dehydroleucodine from Gynoxys verrucosa (Ecuador) caused cell cycle arrest, apoptosis, and DNA damage in human astrocytoma cells (Bailon-Moscoso et al., 2015). Enhanced expression of the cyclin-dependent ki-nase inhibitor (CDKN1A) and protein BAX, as well as the phosphorylation of proteins TP53, TP73, and y-H2AX in cancer cells exposed to dihydrocodeine resulted in cell death (Bailon-Moscoso et al., 2015). Z-ligustilide from Radix Angelicae Sinensis restored Nrf2 gene expression as well as Nrf2 downstream genes (e.g., HO1, NQO1 and UGT1A1) in breast cancer cells (Su et al., 2013). Treatment with Z-ligustilide inhibited DNMT activity in vitro and reduced the level of methylation of the Nrf2 promoter region. This study demonstrated that Nrf2 expression is likely to be epigenetically controlled, and this control was affected by natural compounds, allowing the prevention of carcino-genesis in the TRAMP mouse prostate cancer model (Su et al., 2013). Trichostatin A from actinomycete Streptomyces hygroscopicus is a potent inhibitor of pan-HDAC activity and has been found to induce apoptosis by increasing BAX and CASP3 protein levels, also reducing the telomerase expression (TERT) (Woo et al., 2007). It was discovered that depsipeptide FK228 from Chromobacterium violaceum specifically inhibited class I HDACs, inducing apoptosis of leukemic human cells (Furumai et al., 2002; Konstan-tinopoulos et al., 2006). In addition, FK228 induced the autophagy pathway and translocation of the apoptosis-in-

duced factor (AIF) from mitochondria to the nucleus. This compound was approved by the FDA for the treatment of cutaneous T-cell lymphomas as Istodax.

Our recent study identified three endemic plants from Mauritius affecting the cell cycle of human oesophageal squamous carcinoma cells (Rummun et al., 2019). Treatment with extracts of these plant leaves induced AMPK pathway activation (Rummun et al., 2019). More research is necessary to identify and test the effector molecules in these extracts, as well as their exact mechanisms of action. A promising path to new anticancer therapies is building cell-based systems for phenotypic screening of natural extracts made from various species, e.g., ones used in traditional medicine. For example, such phenotype-based models make it possible to identify small molecules affecting HDACi and DNMTi and other major epigenetic regulators.

Concluding remarks

Reversibility of epigenetic changes could open up exciting opportunities for age-related diseases. An important goal for the future will be the identification of epigenetic drugs to reverse the epigenetic changes which occur as a sign of aging and aging diseases such as cancer. Several specific compounds have been developed which target enzymes responsible for epigenetic changes and are in clinical trials for testing for some age-related diseases, including cancer. A key challenge in this approach will be to develop additional drugs that specifically affect epigenetic pathways and test existing drugs on well-studied animal models.

Overall it is now well established that a variety of natural compounds can be used to modulate epigenetic regulatory mechanisms in tumor cells, enhancing or inhibiting epigenetic regulators to change gene regulation, and therefore control the expression of a large number of proteins and their properties. As a result, such epigenetic interference may induce cell cycle arrest, cell differentiation or cell death via apoptosis, necrosis, autophagy, or mitotic catastrophe in tumor cells as well as shape the microenvironment of the tumor (Yu et al., 2010). However, further in-depth studies are needed to determine the contribution of epigenetic changes caused by natural compounds in various human cancers. A better understanding of epigen-etic targets and pathways altered by natural compounds is needed to develop new strategies in chemoprevention, including their combinations with chemotherapy currently in use, as well as their anti-aging applications.


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