Epigallocatechin gallate (EGCG) is a powerful polyphenolic, chemo-preventive compound isolated from green tea belongs to the catechin class of flavonoids (Singh et al., 2011). The other components of green tea consist of epigallocatechin, epicatechin-3-gallate and epicatechin. There are numerous in vitro, in vivo, and clinical studies that showed potential anti-proliferative, anti-angiogenic, pro-apoptotic and anti-invasive properties of EGCG (Singh et al., 2011). There are significant literatures demonstrating the impact of green tea components in involved in epigenetic modulations in cancer (Henning et al., 2013; Giudice et al., 2018; Jiang et al., 2021). Fang et al., first time revealed that EGCG act as inhibitor of DNA hypermethylation of CpG islands by acting on DNMT (Fang et al., 2003). Another study has shown the profound effects of EGCG on human prostate cancer cells (Paschka et al., 1998). Green tea causes an accumulation of acetylated histone H3 in total cellular chromatin resulting in epigenetically reactivation of p21/waf1 and Bax in prostate cancer cells that leads to cell cycle arrest and apoptosis (Thakur et al., 2012).

Lee et al., examined the regulation of androgen receptor acetylation by measuring histone acetyltransferase activity in androgen-dependent prostate cancer cells treated with green tea catechins (epicatechin, epigallocatechin and epigallocatechin-3-gallate). These catechins induce prostate cancer cell death, suppressed agonist-dependent androgen receptor (AR) activation and AR-regulated gene transcription (Lee et al., 2012). Another report showed that the combinatorial exposures of clofarabine and EGCG or genistein synergistically inhibited the growth of breast cancer cells (MCF7 and MDA-MB-231 cells) and induces apoptosis followed by RARB hypomethylation with consequent manifold increase in RARB, CDKN1A, and PTEN transcript levels. This combination promotes apoptosis and reactivates DNA methylation-silenced tumor suppressor genes in human breast cancer cells with unusual invasive prospective (Lubecka et al., 2018).

EGCG alters the expression of various tumor-suppressor genes by inhibiting DNA methyltransferases and histone deacetylases in human cervical cancer HeLa cells (Khan et al., 2015). Moreover, time-dependent exposure to EGCG resulted in reactivation of well-known tumor-suppressor genes (TSGs) in these cells due to marked transformations in the methylation of the promoter area of these genes (Khan et al., 2015). Recently Ciesielski et al., 2020 studied the impact of EGCG on the histone posttranslational modifications machinery along with chromatin remodeling in human endothelial cells (HMEC-1 and HUVECs origin). Results showed that EGCG increases methylation of both active (H3K4me3) and repressive (H3K9me3) chromatin marks and histone acetylation (H3K9/14ac, H3ac). These results indicated the broad epigenetic potential of EGCG concerning expression and action of epigenome modulators including HDAC5, and HDAC7, CREBP, KMT2A, p300 and LSD1 (Ciesielski et al., 2020).

Another study reported the anticancer mechanism of EGCG via synchronized transcriptional modification of numerous molecular targets through different signaling pathways in Hela cells (Kedhari Sundaram et al., 2020). In this study, transcriptional modulation of several epigenetic modifiers including histone modifiers and DNA methyltransferases (DNMT1, DNMT3A, DNMT3B, AURKA, AURKB, AURKC, PRMT6, PRMT7, KDM4A, KDM5C, HDAC5, HDAC6, HDAC7, HDAC11 and UBE2B) were observed. Downregulation of key signaling moieties of PI3K, Wnt and MAPK pathways, metastasis regulators, cell cycle regulators and pro-inflammatory moieties including CCNB1, CCNB2, TERT, PIK3C2B, PIK3CA, IL6, MMP2, MMP7 and MAPK8 were also detected (Kedhari Sundaram et al., 2020).

Kang et al., demonstrated that EGCG may hamper efficiently IR-induced injury to mouse normal hepatic cells (AML-12), and improve noticeably the radio-sensitivity of mouse hepatoma cells H22 to ⁶⁰Coγ. They also revealed that EGCG played the key task of radio-sensitization on H22 cells because it activates the miR-34a/Sirt1/p53 signaling pathway (Kang et al., 2019). Deb et al., reported that treatment of human prostate cancer cell lines (DUPro and LNCaP) with green tea polyphenols (GTPs) and their major constituent, epigallocatechin-3-gallate (EGCG) induced TIMP3 expression by epigenetic mechanisms (Deb et al., 2019). Furthermore, a clinical study on patients undergoing prostatectomy consuming EGCG showed an increase in plasma TIMP3 levels (Deb et al., 2019).

Dietary flavonoids have potential to modulate non-coding RNAs, including miRNAs in cancer (Ahmed et al., 2020; Yang et al., 2020; Singh et al., 2021). In a recent in vivo study by Kang et al., revealed that oral administration of EGCG suppresses miR483–3p induced metastasis of hepatocellular carcinoma (Kang et al., 2021). EGCG modulate non-coding RNAs and inhibit tumor growth by targeting LINC00511/miR-29b/KDM2A axis in gastric cancer (Zhao et al., 2020). EGCG-capped gold nanoparticle significantly increased expression of tumor suppressor let-7a and miR-34a miRNAs (Mostafa et al., 2020).

Flavonols (3-hydroxylavones) are most prevalent flavonoids in food. Quercetin, myricetin, kaempferol and fisetin are the most common plant flavonols found in many vegetables and fruits, e.g., onions, apples, strawberries etc. The defensive impacts of quercetin on human health are facilitated by multidimensional, pleiotropic action still from an epigenetic perspective (Russo and Ungaro, 2019).

Quercetin modulates the expression of various chromatin modifiers and declines the activity of HDACs, DNMTs and HMTs in a dose-dependent manner in human cervical cancer (HeLa) cells (Kedhari Sundaram et al., 2019). It also downregulated global DNA methylation concentrations in a dose- and time-dependent manner and tested tumor suppressor genes showed steep dose-dependent decrease in promoter methylation with the restoration of their expression. Quercetin along with BET inhibitors promoted apoptosis and decreases the cell proliferation and sphere-forming ability by pancreatic cancer cells. It was also evidenced that quercetin also mediates some anti-tumor effects with the help of hnRNPA1 which is a nuclear protein well-known to monitor mRNA export and mRNA translation of anti-apoptotic proteins (Pham et al., 2019). Quercetin also induced let-7c which decreased pancreatic tumor growth by posttranscriptional activation of Numbl and indirect inhibition of Notch (Nwaeburu et al., 2016); Zheng et al. (2014) reported that nanoliposomal quercetin combined with butyrate modulated aberrant epigenetic alteration in Eca9706 cells via epigenetic-NF-κB signaling. In this study reverse expressions of global DNMT1, HDAC1, NF-κB p65 and Cyclin D1 were down-regulated, although expressions of p16INK4α and caspase-3 were up-regulated. Furthermore, quercetin modulate miR-1-3p/TAGLN2 (Wang et al., 2021b), miR-197/IGFBP5 (Hu et al., 2020), miR-16–5p/WEE1 (Wang et al., 2020a), miR-22/WNT1/β-catenin (Zhang et al., 2019a), miR-16/HOXA10 (Zhao et al., 2019), TP53/miR-15/miR-16 (Ahmed Youness et al., 2018) axes as well as miR15a/16 (Ramos et al., 2021), miR-200b-3p (Nwaeburu et al., 2017), miR-145 (Zhou et al., 2015), and miR-146a (Tao et al., 2015) in various cancers.

Kaempferol (3,4′,5,7-tetrahydroxyflavone) is a potential HDAC inhibitor and an anti-cancer agent against many types of cancers (Imran et al., 2019). Berger et al., reported first time that kaempferol has a distinctive epigenetic activity by inhibition of HDACs (Berger et al., 2013). The in-silico docking analysis fits kaempferol into binding pocket of HDAC2, 4, 7 or 8 and in vitro profiling of all conserved human HDACs of class I, II and IV demonstrated that it inhibited all tested HDACs. Furthermore, kaempferol stimulates hyperacetylation of histone H3 in HepG2 and Hep3B (hepatoma cancer cell lines) as well as on HCT-116 (colon cancer cell line) (Berger et al., 2013). Kaempferol induces autophagic cell death via IRE1-JNK-CHOP signaling and inhibiting HDAC/G9a axis in gastric cancer cells (Kim et al., 2018). In lung cancer A549 cell, kaempferol induces miR-340 expression (Han et al., 2018) which is known to induce apoptosis and inhibit cell proliferation in NSCLC (Fernandez et al., 2014).

Flavonol, fisetin is also a powerful anticancer agent, used to inhibit different stages of cancer cells, induce apoptosis, inhibit cell growth, prevent cell cycle progression, cause PARP cleavage, and modulate the expressions of Bcl-2 family proteins in various cancer cell lines (Imran et al., 2020). It also suppresses the activation of the ROS/ PKCα/ p38 MAPK and ERK1/2 signaling pathways, down-regulates the level of the oncoprotein securin and lowers the NF-κB activation (Pal et al., 2016). Recently, Ding et al., revealed that fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation (Ding et al., 2020).

Flavones are a group of flavonoids that contain the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) having diverse pharmacological properties and are commonly found in herbs such as celery, parsley and in almost all edible cereal species. Apigenin, luteolin, tangeretin, chrysin, Tricin, baicalein, rhoifolin and 6-hydroxyflavone are some common flavones (Barreca et al., 2020).

Pandey et al. (2012) reported first time that apigenin inhibits class I HDACs, particularly HDAC1 and HDAC3, alters chromatin to induce growth arrest and apoptosis in human prostate cancer cells. Apigenin inhibited MDA-MB-231 breast cancer cell proliferation and tumor growth by induction of G2/M arrest and histone H3 acetylation-mediated p21 expression (Tseng et al., 2017). Apigenin enhances miR-16 (Chen et al., 2016) and miRNA215–5p (Cheng et al., 2021) expression to inhibits glioma and colon cancer growth respectively, as well as chemo-sensitize doxorubicin-resistant liver cancer cells by targeting miR-520b/ATG7 axis (Gao et al., 2018).

Recently Wu et al. (2021) discovered that luteolin inhibited the proliferation and metastasis of androgen receptor-positive triple-negative breast cancer cell by epigenetic regulation of MMP9 expression through a reduction in the levels of AKT/mTOR-inducing H3K56Ac and H3K27Ac. Earlier it was also revealed that luteolin suppresses the metastasis of triple-negative breast cancer, downregulates the ß-catenin expression for reversing epithelial-to-mesenchymal transition (Lin et al., 2017). In colorectal cancer cells Luteolin induces apoptosis by the downregulations of UHRF1, calpain, and DNMT1 expressions. This research further suggests that calpain might be involved in the epigenetic code inheritance by regulating the epigenetic integrator UHRF1(Krifa et al., 2014). In human prostate cancer (PC-3) cells, Luteolin and gefitinib regulate cell cycle pathway genes (CCNA2, CCNE2, CDC25A, CDKN1B, and PLK-1) through a mutual mechanism involving EGFR-associated tyrosine kinase (Markaverich et al., 2010). Authors suggested that these phytochemicals likely modulate the epigenetic control of gene expression as previously shown by their group that luteolin interacts with type II binding sites on histone H4 (Shoulars et al., 2010). Recently, Farooqi et al. and Mishan et al. have systematically reviewed the potent ability of luteolin to modulate miRNA expression in various cancers (Farooqi et al., 2020; Mishan et al., 2021). A derivative of tangeretin prevents the progress of human prostate cancer cells by epigenetically restoring p21 gene expression and inhibits cancer stem-like cell proliferation (Wei et al., 2019).

Baicalein (5,6,7-trihydroxyflavone) suppresses cancer cell proliferation, cell cycle arrest and induces apoptosis in human prostate, breast, T24 bladder and myeloma cancer cells (Gao et al., 2016). Lai et al., studied the epigenetic role of baicalin hydrate in nasopharyngeal carcinoma (NPC) and identified that it inhibits NPC cell growth both in vivo and in vitro. Furthermore, instead of DNA methylation, baicalin hydrate increased of m6A RNA methylation and promoted Suv39H1 gene splicing. (Lai et al., 2018). It is also documented that baicalin improves the developmental proficiency of in vitro cultured mouse embryos through reticence of cellular apoptosis and HSP70 expression and enhancement of DNA methylation (Qi et al., 2016). Several recent studies have shown that baicalein modulate the expression of miR-183 (Lei et al., 2021), miR-139–3p and miR-196b-5p (Ma et al., 2021), and miR-25 (Örenlil Yaylagül and Ülger, 2020) in various cancers.

Flavanones are aromatic, colourless ketones mainly present in citrus fruits (Barreca et al., 2017). Hesperetin, isosakuranetin, naringin, naringenin, isosakuranetin and eriodictyol and their particular glycosides are some main flavanones (Khan et al., 2013). Hesperetin is a common citrus flavanone that endorses DOT1L degradation and decreases histone H3K79 methylation to prevent gastric cancer metastasis, showing its epigenetic effect (Wang et al., 2021a). Natural flavonolignan, silibinin is the most effective phytochemical of silymarin. It is active both alone and in combination with other chemotherapeutic and epigenetic agents, substantially inhibit the growth of different cancer cells. It synergizes with DNA methyltransferase and histone deacetylase inhibitors in upregulating e-cadherin expression, also inhibits the invasion and migration of human non-small cell lung cancer cells. These results are highly substantial since failure of E-cadherin and metastatic dispersed of the illness via epithelial-to-mesenchymal transition is associated with poor prognosis and high mortalities in this type of cancer cells (Mateen et al., 2013). In human prostate cancer (DU145 and PC3) cells, silibinin reduces gene expression levels of EZH2 accompanied by an increase in H3K27me3 levels (Anestopoulos et al., 2016). Such responses were dependent on decreased expression levels of phosphorylated EZH2 (ser21) and phosphorylated Akt (ser473). Moreover, it also exerted other epigenetic impacts involving, decrease histone deacetylases 1–2 (HDACs1-2) expression levels while it increases total DNA methyltransferase (DNMT) activity, proving that it induces epigenetic alterations in human prostate cancer cells. (Anestopoulos et al., 2016). Hossainzadeh et al. reported that silibinin encapsulated in polymersome nanoparticles supress the expression of oncogenic miRNAs miR-125b and miR-182 (Hossainzadeh et al., 2019).

Naringenin (4,5,7 trihydroxyflavanone) is an aglycone form of naringin found in citrus fruits. When it combined with suberoylanilide hydroxamic acid (HDAC inhibitor), synergistically improved transamidation activity and suberoylanilide hydroxamic acid induced cytotoxicity in neuroblastoma cells which showed no cytotoxicity on normal non-malignant cells (Ling et al., 2012). This suggest that naringenin possesses effective histone deacetylase inhibitory activity; however, more comprehensive studies are needed understand its epigenetic potential.

Isoflavones are naturally occurring isoflavonoids, mainly found in legumes, soy beans, and soy foods. They have several potent pharmacological activities like anti-inflammatory, antioxidant, antimicrobial, and anticancer (Panche et al., 2016). It is also well evidential that they exert estrogenic and/or antiestrogenic impacts. Isoflavones are considered as chemoprotective in nature and used in various type of alternative therapies for a broad range of hormonal ailments including several types of cancers, osteoporosis, menopausal problems and cardiovascular diseases (Taku et al., 2011; Vitale et al., 2012; Qin et al., 2013; Sathyapalan et al., 2018; Nakai et al., 2020). There are conflicting reports that isoflavones disrupt endocrine function; however, it appears the most common harmful effect is mild and appears at the gastrointestinal level (Křížová et al., 2019; Gómez-Zorita et al., 2020). Some common examples of isoflavones are Daidzein, Genistein, Genistin and Glycitein.

Among all isoflavones, genistein is the most potent and biologically active phytochemical, demonstrating different in vivo and in vitro anticancer and anti-proliferative effects on numerous types of human cancers (Spagnuolo et al., 2015). Prostate cell lines (DU-145 and PC-3) when treated with soy phytoestrogens, genistein and daidzein, cause decrease in DNA methylation at EPHB2, BRCA1 and GSTP1 promoters (Adjakly et al., 2011). Karsli-Ceppioglu et al., reported that phytoestrogens (genistein and daidzein) modulate genome-wide DNA methylation status in prostate cancer. They found that methylation profiles of 58 genes have been modified by genistein and daidzein treatments in prostate cancer DU-145 and LNCaP cell lines (Karsli-Ceppioglu et al., 2015). Notably, the methylation frequencies of the hTERT, MAD1L1, KDM4B and TRAF7 genes were remarkably altered by genistein treatment. Genistein regulates miRNAs expression in pan cancer (Javed et al., 2021). In head and neck cancer, genistein activate miR-34a/RTCB axis that results in ROS-associated apoptosis, decrease in stemness properties, and inhibition of EMT (Hsieh et al., 2020). Recently, Imai-Sumida et al., reported that genistein suppress kidney cancer by repressing HOTAIR/chromatin remodeling pathways (Imai-Sumida et al., 2020). Conversely, Allred et al., reported that dietary genistin as well as genistein can stimulates estrogen-dependent breast cancer cell growth in vivo (Allred et al., 2001). These conflicting reports compel a need for in-depth mechanistic studies to understand the biological effects of these dietary compounds, including their epigenetic modifying potentials, cytotoxicity, and anticancer properties.

Anthocyanidins are the sugar-free counterparts of anthocyanins and are highly important water-soluble pigments found in plants. Among all anthocyanidins, delphinidin is the most potent and abundant flavonoid found in pigmented fruits (especially blueberry) and vegetables (Khoo et al., 2017).

Kuo et al., reported that delphinidin epigenetically re-activates Nrf2-ARE pathway and prevents neoplastic transformation of mouse skin JB6 P+ cells (Kuo et al., 2019). The Nrf2-ARE pathway activation was associated with demethylation of 15 CpG sites in the mouse Nrf2 promoter region between nucleotide -1,226 and -863 from the transcription start site. The decreased CpG methylation proportion in the Nrf2 promoter region was consistent with detected declines in the protein expression of DNA methyltransferases 1 (DNMT1), DNMT3a, and class I/II histone deacetylases (HDACs) (Kuo et al., 2019). Jeong et al., identified the epigenetic modulators that mediate the apoptotic effect of delphinidin (major anthocyanidin compound) in human prostate cancer cells (Jeong et al., 2016). They treated these cancer cells with delphinidin and observed an increase in caspase-3, -7, and -8 activity along with an increased histone deacetylase activity. Amongst all class I HDACs, the activity of HDAC3 was exclusively prevented by delphinidin. Moreover, the apoptosis induced by delphinidin was reliant on caspase-mediated cleavage of HDAC3, resulting in the stabilization and acetylation of p53. They also observed that this anthocyanidin effectively upregulated pro-apoptotic genes that are definitely regulated by p53 and also downregulated numerous anti-apoptotic genes (Jeong et al., 2016). Delphinidin targets HOTAIR/miR-34a axis to suppress the breast carcinogenesis (Han et al., 2019) and inhibits colorectal cancer metastasis by inducing miR-204–3p expression (Huang et al., 2019).