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Rajendran, P.;  Abdelsalam, S.A.;  Renu, K.;  Veeraraghavan, V.;  Ammar, R.B.;  Ahmed, E.A. Polyphenols for Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/29627 (accessed on 15 December 2025).
Rajendran P,  Abdelsalam SA,  Renu K,  Veeraraghavan V,  Ammar RB,  Ahmed EA. Polyphenols for Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/29627. Accessed December 15, 2025.
Rajendran, Peramaiyan, Salaheldin Abdelraouf Abdelsalam, Kaviyarasi Renu, Vishnupriya Veeraraghavan, Rebai Ben Ammar, Emad A. Ahmed. "Polyphenols for Cancer" Encyclopedia, https://encyclopedia.pub/entry/29627 (accessed December 15, 2025).
Rajendran, P.,  Abdelsalam, S.A.,  Renu, K.,  Veeraraghavan, V.,  Ammar, R.B., & Ahmed, E.A. (2022, October 17). Polyphenols for Cancer. In Encyclopedia. https://encyclopedia.pub/entry/29627
Rajendran, Peramaiyan, et al. "Polyphenols for Cancer." Encyclopedia. Web. 17 October, 2022.
Polyphenols for Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/ijms231911712

Polyphenols play a major role in mammalian epigenome regulation through mechanisms and proteins that remodel chromatin. In fruits, seeds, and vegetables, as well as food supplements, polyphenols are found. Compounds such as these ones are powerful anticancer agents and antioxidants.

cancer polyphenol epigenetics

1. Introduction

Epigenetics is the study of how genes and their products affect an organism’s phenotype [1]. Since the discovery of DNA, epigenetics has not received much attention. In the 1980s, however, studies of chromatin structure made epigenetics respectable after being shrouded in the shadows [2]. In 1987, Robin Holliday redefined epigenetics as nuclear inheritance without DNA sequence differences [3]. It offers possible explanations for cellular differentiation and parental imprinting in mammals, and it enables genetics and developmental embryology to be integrated [4]. Furthermore, epigenetic modifications play a crucial role in developmental patterning, biological processes, and pathology [5][6][7]. In mammalian cells, DNA methylation and histone modifications induce chromatin remodeling, leading to cellular phenotype changes [8][9][10][11]. Diverse epigenetic changes occur in cancer cells in the early stages of tumor development [12]. These epigenetic modifications of chromatin are inherited and reversible, so they could be used to develop drugs targeting the epigenome which could help treat cancer [13][14][15]. The use of new therapeutic drugs and personalized treatment leads to improved patient survival. Dietary supplements have been combined with some of these treatments [16][17][18]. Diets high in vegetables and fruits have been proven to reduce the risk of cancer. This is because they regulate the expression of oncogenes and tumor suppressor genes [19]. Dietary supplements might be an alternative cancer treatment.

2. Oxidative DNA Damage and Polyphenols

Polyphenols have antioxidant properties which as a therapeutic action against cancer. It is found that polyphenol has a dominant antioxidant that mitigates oxidative stress from pathological conditions such as cancer. Polyphenol can scavenge ROS and act on free radicals. This is due to the presence of aromatic rings, the presence of hydroxyl groups in a different region, and has more conjugated system [20]. Polyphenol scavenges Reactive Oxygen Species (ROS) and mitigates the biomolecule oxidative damage [21][22]. Polyphenols with antioxidant capacity suppress the signaling pathways involved in oxidative stress generation at a molecular level. Consumption of a polyphenol diet increases the activity of the antioxidant and inhibits the peroxidation of lipids and cyclooxygenase (COX) pathways [23]. Increased levels of free radical production such as ROS and LPO with oxidative stress cause damage to the tissues inclusive of DNA and increases the possibility of cancer occurrence. Increased ROS level is due to exogenous, antioxidant defense, and endogenous sources. The exogenous sources include X-rays, UV light irradiation, the action of metals, toxins, and γ rays, drugs, and solvents; endogenous sources include peroxisomes, metabolism of cytochrome P450; reactions in mitochondria; and activation of inflammation. This exogenous and endogenous source of ROS is important for oxidative stress-mediated ROS production causes damage to the cell, and alters the signaling pathway, which further causes cancer [24]. Damages to the DNA can cause errors in the replication, arresting transcriptional activities, instability of the DNA damage, and further causes cancer [25][26]. Different studies show a reduction in endogenous DNA damage and protection from ex vivo DNA damage [27]. A diet such as vegetables and fruits has a high content of polyphenols which includes quercetin, ellagic acid, catechins, naringenin, and resveratrol. This polyphenol can decrease the risk of cancer. Polyphenols have a chemopreventive action which includes the involvement of antiestrogenic, arresting cell cycle, proliferation against cancer cells, resistance to the oxidative stress, induction of apoptosis, detoxification enzyme activation, regulation of the host immune system, and cellular signaling improvement in the cancer condition [28]. Polyphenols show protection from cancer when combined with DNA-damaging agents. Polyphenols impair the metabolism of pro-carcinogen by altering the level of enzyme cytochrome P450 which plays an important role in the stimulation of cancer [29]. Polyphenol and quercetin have properties of anti-cancer action by reducing free radical-ROS scavenging activity [30]. The polyphenols present in black tea such as theaflavins, EGCG, and thearubigins have effective properties of anti-cancer [31][32][33]. The catechins present in the tea can prevent cancer by impairing intraepithelial prostate lesions converting them into cancer and decreasing the cancer cell apoptosis, thereby it inhibits carcinogenesis [34]. The flavonoids like catechins, anthocyanins, flavanols, flavanones, flavones, and isoflavones, have a capacity for free radicals neutralization via scavenging ROS and impairs the risk of cancer by cellular growth arrest in cancer cells [35]. There are different types of cancer such as prostate, endometrial, epithelial, breast cancer and colon cancer are mitigated by polyphenols [36]. Resveratrol has an anti-cancer property via an antioxidant defense mechanism which impairs the hydroperoxidase level, matrix metalloproteinase level (MMP-9), Akt signaling pathway, NF-KB pathway, cycloxygenase pathway, protein kinase C, Bcl-2 level and focal adhesion kinase [37].

3. Human Cancer and DNA Methylation

In cancer, epigenetic changes include genome-scale methylation changes, hypermethylation in specific loci, and dysfunction of histone-modifying enzymes. Changes in DNA methylation are good biomarkers since they can be detected and quantified [23][38][39]. Many studies have found DNA methylation patterns specific to liver cancers, including genome-wide studies [40][41][42][43][44][45]. According to DNA methylation and transcriptome mapping in human tumors, a lot of genes are hypomethylated and expressed more, and a lot of genes are hypermethylated and underexpressed. The genes induced by epigenetics were found to be involved in cellular transformation and differentiation, tumor growth, and metastasis. Apoptosis, cell adhesion, and cell cycle progression genes are repressed [46][47][48]. Even though genome-wide DNA methylation studies are a hot topic, there are a few caveats that urge caution about the clinical and biological significance of the data [49]. Most importantly, tumors have a lot of cellular heterogeneity, so observed differences in DNA methylation patterns might just be due to differences in tumor cell numbers, rather than being an epigenetic signature. The DNA methylation profiling needs to be performed on small numbers of histologically verified tumor cells sorted by high-speed cell sorting or laser dissection microscopy. Another caveat is that researchers shouldn’t assume a simple relationship between DNA methylation and gene expression, even if transcriptome data indicates that. In vivo experiments would need to manipulate DNA methylation site-directedly and demonstrate transcription rate changes (Table 1).
Table 1. Polyphenols on DNA methylation and histone modification.
Polyphenols Molecular Mechanism Pre Clinical Model Target Gene
  DNA methylation
Curcumin DNMT inhibitor Leukemia, esophageal NA
Epicatechin, epicatechin-gallate, epigalocatechin-3-gallate DNMT inhibitor Lung, colon cancer cells, esophageal, oral, breast cancers RAŘ, MGMT, MLH1, CDKN2A, RECK, TERT, RXⱤ, CDX2, GSTP1, W1F1
Quercetin DNMT inhibitor Breast, colon, esophageal cancers CDKN2A
Resveratrol DNMT inhibitor Breast, Lungs cancers NA
  Histone modifications
Curcumin HAT and HDAC inhibitor anti-inflammatory
anticancer, antioxidant,
antiproliferative		 GATA4, EOMES, GZMB, PRF1,H3/H4 deacetylation
Epicatechin, epicatechin-gallate, epigalocatechin-3-gallate HAT inhibitor antioxidant,
anticancer,
anti-inflammatory		 NF-kB, IL-6, BMI-1, EZH2, SUZ12, H3K27 trimethylation, H3/H4 acetylation
Quercetin SIRTI activator HAT inhibitor anti-migration,
anticancer, antiproliferative,
antidiabetic, antioxidant		 Inflammatory diseases
Resveratrol SIRTi activator anti-migration,
anticancer, antiproliferative,
antidiabetic, antioxidant		 TNF-˛, IL-8, RBP

4. Cancer and Histones

DNA is packed into chromatin around an octamer of histones in a chromosome. A nucleosome is a repeating unit of chromatin that is made up of 150 base pairs of DNA and an octamer of histones, H2A, H2B, H3, and H4 [49][50][51][52]. Histone tails are targets for post-translational modifications, including acetylation, methylation, phosphorylation, and ubiquitination [53][54]. DNA modifications can turn the transcription of genes on or off, which affects the accessibility of transcription factors by adjusting how tightly DNA is bound to histones. HATs, which “write” the acetyl mark on histones, are responsible for histone acetylation. By counteracting the positive charge of histones, it loosens the connection between histones and DNA. In contrast, histone deacetylases (HDACs) “erase” those acetyl groups, resulting in tight DNA coiling around the histones, making chromatin transcriptionally inactive. Histone methylation is associated with either transcriptionally active or closed chromatin depending on where the lysine is methylated [55]. The trimethylation of histone 3 lysine 27 (H3K27me3), for example, is associated with transcriptional repression, whereas trimethylation of histone 3 lysine 4 is associated with gene activation [56][57]. Cancer patients with high levels of trimethylated histone H3 lysine 4 (H3K4me3) have a poor prognosis. H3K27me3 levels were linked to poor prognosis and tumor aggressive features including vascular invasion, large tumor sizes, multiple tumors, and poor differentiation in another study [56][58][59]. To fully understand the role of these specific DNA-protein modifications in cancer, further studies using more precise detection methods, such as ChIP-sequencing, will be needed.

5. Inhibitors of DNA Methylation

The epigenome is reprogrammed as soon as embryogenesis begins because DNA methylation decreases. Methylation of DNA requires methylating enzymes, so cellular replication without these enzymes leads to significant demethylation of daughter cells and gene reactivation. This approach has a therapeutic ratio when applied to cancer cells; normal cells usually survive hypomethylation, whereas cancer cells usually die when it occurs, perhaps because they are dependent on gene silencing.
DNA hypomethylation only happens with cytosine analogs with 5’ modifications of the ring. Nucleoside and cytosine analogs do not directly affect DNA methylation. It was determined that the ability of these two main analogs to target DNA methyltransferases (DNMTs) for degradation was attributed to their ability to trap DNA methyltransferases (Table 1). In the absence of these enzymes, DNA synthesis results in hypomethylation in daughter cells, which in turn leads to the reactivation of silenced genes. Some other 5’ modified nucleoside analogs have been described in preclinical or early clinical studies [60]. Inhibiting DNA methylation in cancers works, at least in part, by inhibiting DNA methylation.

6. Inhibitors of Histone Modification

Inhibitors of histone deacetylase (HDACi) decrease HDAC activity, block acetylated histone aggregation, and promote autosomal acetylation. HDACi promotes cancer cell differentiation, induces apoptosis, and inhibits angiogenesis through many mechanisms, including cell cycle arrest, apoptosis, autophagy, and differentiation. HDACi are classified into four classes based on their chemical. In addition to in vitro and in vivo studies, hydroxamates and aliphatic acids have also been tested in clinical trials as a new treatment strategy for hepatobiliary cancer [61][62][63][64]. Panobinostat, trichostatin A, vorinostat, and belinostat are hydroxamates that block HDAC activity by binding to Zn2+ at the HDAC binding site. Besides aliphatic acids, sodium butyrate and valproic acid (VPA) inhibit class I HDACs as well [65][66]. For example, this occurs with VPA, sodium butyrate, and TSA. By downregulating cyclins A and D1 and upregulating P21, VPA could induce cell cycle arrest [67]. Additionally, sodium butyrate upregulated p21 and p27 protein expression [68][69][70]. Furthermore, TSA causes G2/M-phase arrest and G0/G1 arrest in hepatoma cells [71][72]. The fact that apoptosis plays an important role in tumor development makes it an obvious target for cancer therapy. HDACi promotes apoptosis in cancer cells. In addition, HDACi promotes apoptosis by different mechanisms; for example, VPA activates TRAIL-associated cell death and intrinsic apoptosis by upregulating cleaved caspases 3 and 9 [73]. Specifically, TSA upregulates bax and cleaved caspase 3 and downregulates BCL-2 in cancer cells [74][75]. Further, it has been found that HDACi can induce autophagy-mediated cell death, and cancer cell lines showed autophagosome formation, maturation, and aggregation when exposed to panobinostat. Several inhibitors of angiogenesis have been found to interact with HDACi in a synergistic way to inhibit hepatobiliary cancers [76][77]. Some clinical trials have tested HDACi’s anticancer effects, especially when combined with sorafenib.

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Peramaiyan Rajendran , Salaheldin Abdelraouf Abdelsalam , Kaviyarasi Renu , Vishnupriya Veeraraghavan , Rebai Ben Ammar , Emad A. Ahmed
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Update Date: 17 Oct 2022
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