DNA methylation is responsible for controlling gene expression and interacting with the nucleosomes that control DNA packaging, and it can influence entire DNA domains. It is a chemical, biological modification where cytosine residues are methylated at a 5′position. This modification mainly occurs at cytosine residues present in GC dinucleotide-rich regions clustered together to form the CpG islands spanned the 5′end region of several genes (Issa and Kantarjian, 2009).

The human genome contains approximately 28 million CpG sites. Under normal circumstances, most CpG islands, especially within the promoter region, are unmethylated except in the case of X-inactivation, genome imprinting, and repression of transposons. DNA methylation occurs during the early embryonic stages by a set of distinct enzymes called DNA methyltransferases (DNMTs) (Bird, 2002). DNA methyltransferases catalyze the formation of 5-methyl cytosine that involves the transfer of a methyl group from S-adenosyl-L- methionine (SAM) to the 5′position of the cytosine residue in CG dinucleotide (Santi et al., 1983). DNMT1, DNMT3A, and DNMT3B are the three major DNMTs involved in DNA methylation in mammals. Maintenance of methylation patterns during replication is one of the critical functions of DNMT1. During replication, DNMT1 adds a methyl group to hemi methylated CpG dinucleotides in the daughter strand as it shows 5–30 times greater affinity for hemi methylated substrates. In contrast, DNMT3A and DNMT3B are de novo methyltransferases exclusively involved in the methylation of previously unmethylated DNA sequences (Okano et al., 1999; Bestor, 2000). To ensure methylation, DNMTs must have access to the DNA that can be gained via perturbation of chromatin structure by specific chromatin remodeling proteins (As shown in Figure 3) (Baylin et al., 2001).

In cancer, hypermethylation of CpG islands in the promoter sequence of some genes results in gene silencing by suppressing the transcriptional activity of tumor suppressor genes (Dehan et al., 2009). For instance, promoter hypermethylation of CpG sites of tumor suppressor genes like RARβ and RASSF1A can induce breast cancer development (Van Hoesel et al., 2013). Certain studies of malignant and tumor cells have shown hypomethylation of DNA sequences at CpG sites that can cause conformational and functional alterations in chromosomes (Gama-Sosa et al., 1983). In cancer there are several natural compounds known to influence the DNA methylation as listed in Table 2 in most of the cases by a single publication.

An increasing list of different phytocompounds targeting DNA methylation at distinct genes in various cancer cell lines has been discovered in the last two decades. This section summarizes the phytocompounds that have the potential to act as DNA methylation inhibitors and activators altering the tumor suppressor gene expression.

Apigenin, a polyphenol, has been shown to reduce the methylation of CpG sites in the Nrf2 promoter region, which contributed to increased mRNA levels of downstream genes. Nrf2 codes a transcription factor that regulates antioxidant enzymes. Furthermore, apigenin also decreased DNMT expression in mouse skin cancer cell line (Paredes-Gonzalez et al., 2014).

Neurog-1 gene plays a critical role in neuronal differentiation. Curcumin-induced treatment reported demethylation of 14 CpG sites of Neurog-1 promoter and downstream gene reactivation in prostate cancer cell line (Shu et al., 2011). BRCA1, a DNA repair gene, critically regulates cell cycle checkpoints and transcription. Triple-negative breast cancer (TNBC) cell lines were treated with curcumin, which caused the upregulation of the TET1 gene that promoted the BRCA1 promoter’s hypomethylation. Furthermore, it induced upregulation of DNMT3 that resulted in suppressed expression of proto-oncogene SNCG (Al-Yousef et al., 2020). Curcumin treatment reactivated RARβ by causing promoter hypomethylation in lung cancer cells. The treatment further resulted in increased RARβ protein and mRNA expression. Curcumin treatment also induced downregulation of DNMT3b, resulting in decreased expression of DNMT3b mRNA levels (Jiang et al., 2015).

Epigallocatechin 3-gallate (EGCG), a polyphenol obtained from green tea, is one of the most studied chemo preventive agents. Besides EGCG, epigallocatechin and epicatechin are also among the major constituents of green tea. Several studies have documented numerous medical benefits of EGCG; regulation of cancer cell growth is one of them (Shankar et al., 2007). According to an in vitro study, catechol inhibits DNMT activity by directly inhibiting DNMTs or by causing o-methylation of SAM by methyltransferases that result in increased SAM levels. Treatment of esophageal cancer cell lines with EGCG exhibited unmethylation specific bands for tumor suppressor p16INK4a, retinoic acid receptor β (RARβ), MGMT, and DNA repair hMLH1 genes. Furthermore, it demonstrated that EGCG reactivated the RARβ gene in prostate cancer and esophageal cancer cell lines (Fang et al., 2007). In another study, breast cancer cell lines reported downregulation of DNMT expression and restoration of the tumor suppressor gene SCUBE 2 expression, when treated with EGCG, that resulted in increased E-cadherin expression and suppression of cell migration and invasion (Sheng et al., 2019).

Genistein-induced treatment of HeLa cells reduced promoter 5′CpG methylation levels of various tumor suppressor genes involved in PI3K and MAPK signaling. The restoration of transcription levels of earlier hypermethylated genes (mentioned in Table 2) can be correlated to a decrease in methylation levels (Sundaram et al., 2019). In a triple-negative breast cancer cell, silencing of BRCA1 is often a result of overexpression of the aryl hydrocarbon receptor. In vivo study of the mammary gland of adult mice demonstrated that lifelong treatment with genistein reduced BRCA1 CpG methylation in the offspring’s mammary tissue (Donovan et al., 2019). Treatment with genistein and daidzein resulted in re-expression of BRCA1, EPHB2, and Glutathione S-transferase pi 1 (GSTP1) in prostate cancer cells, suggesting a preventive effect of soy phytoestrogens against prostate cancer (Adjakly et al., 2011).

GSTP1 encodes for a detoxifying enzyme that protects cells from genome-damaging stresses caused by reactive chemical species. Lycopene induced promoter demethylation of GSTP1 in prostate cancer cells, increasing the mRNA and protein levels. Further treatment with lycopene also decreased the protein levels of DNMT3a. Fu et al. (2014).

The hypermethylated RASSF1A promoter in prostate cancer cell line, when treated with phenethyl isothiocyanate (PEITC), reported a decrease in methylation of CpG sites by an average of 90% compared to untreated cells with 98% of methylation at 16 CpG sites. Promoter demethylation of the tumor suppressor gene RASSF1A correlated with decreased mRNA expression of DNMT1 and DNMT3A when treated with PEITC (Boyanapalli et al., 2016). PEITC induced CpG demethylation in GSTP1 promoter of LNCAP cells in a concentration-dependent manner and was almost similar or higher than the commonly used DNMT inhibitor 5-Aza-2′-deoxycytidine. On further analysis by pyrosequencing tool, it was revealed that PEITC treatment significantly reduced CpG methylation at positions 1 and 3 from 89.5% to 73.2% and 61.8%–6.5%, respectively, that was higher than the demethylating activity of 5′-Aza (Wang et al., 2007).

Quercetin inhibited the DNMT activity and resulted in the restoration of various tumor suppressor genes that were earlier hypermethylated at 5′CpG promoter sites in cervical cancer cells (mentioned in Table 2). Furthermore, in silico studies revealed that quercetin competitively inhibit DNMTs by binding to its catalytic active sites (Kedhari Sundaram et al., 2019). Quercetin treatment decreases the methylation levels of P16INK4a, Er-beta, and RASSF1A genes in bladder cancer cell lines. Furthermore, quercetin treatment inhibited the expression of mutant p53 and survivin proteins. P53 maintains cell cycle regulation, DNA repair, and apoptosis, and any alteration in p53 happens to decrease genomic stability and DNA repair. While Survivin acts as antagonists by inhibiting antiapoptotic pathways and promoting mitotic progression (Ma et al., 2006). In vitro and in vivo studies revealed that quercetin induced demethylation of highly methylated promoter sites of apoptosis-related genes BCL2L11 and DAPKlin, leukemia cell lines (Alvarez et al., 2018).

A study on rodent’s mammary tumor treated with resveratrol indicated a decrease in DNMT 3b expression. The study further reported that 26% of rats developed tumors when treated with a low dose of resveratrol, while only 18% developed tumors with high dose compared to 33% in the control group (Qin et al., 2014). Resveratrol upregulated the expression of cellular retinoic acid binding protein 2 (CRABP2) that mediates retinoic acid anticancer pathways in thyroid cancer cell lines by partial demethylation of CpG promoter sites. In addition, resveratrol significantly decreased DNMT1 and DNMT3A expression (Liu X. et al., 2019).

Sulforaphane treatment downregulated DNMT expression and can mediate promoter demethylation in prostate cancer cells (Wong et al., 2014). In colon cancer cells, sulforaphane inhibited the expression of DNMT1 and increased Nrf2 protein expression by decreasing the methylation of Nrf2 promoter region (Zhou J. W. et al., 2019).

In TNBC cells, withaferin A induced hypermethylation of tumor-promoting genes ADAM8, PLAU, TNFSF12, GSTM1, ME3, and hypomethylation of GLRX2, GFPT2, STX11, and VGF (vel Szic et al., 2017).

The reversible epigenetic process of DNA methylation regulates chromosomal integrity, tissue differentiation, and gene expression throughout embryogenesis. However, any aberrant epigenetic modifications during these processes can lead to tumorigenesis. As extensively discussed above, numerous studies provide evidence that these abnormal modifications can be undone by a plethora of phytocompound treatment. Phytocompounds targeting DNA methylation are listed below in Table 2.

Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group to the ε-amino group of the lysine side chains utilizing the cofactor acetyl CoA, thereby weakening the DNA and histone interactions. HATs have been classified into two- Type-A and Type-B. Further, HATs can be divided into three major categories- GNAT, MYST, and p300/CBP (Bannister and Kouzarides, 2011). Acetylation at K5 and K12 of newly synthesized H4 histones is catalyzed by type-B HAT (HAT1), along with specific sites at H3 histone (Kouzarides, 2007). Predominant transcriptional repressors, histone deacetylases (HDACs), catalyze the reverse lysine acetylation, thus restoring the positive charge of lysine and stabilizing the chromatin structure. The HDACs have been categorized into four major classes: classes I, II, III, and IV. HDACs 1, 2, 3 and belongs to class I HDACs, while class II comprises of HDACs 4, 5, 6, 7, 9, and 10; and only HDAC11 belongs to class IV HDACs. Sirtuins, another name for class III HDACs, are structurally distinct from the other classes and require a cofactor (NAD⁺) for its activity (Mottet and Castronovo, 2008).

Lysine and arginine residues are mostly favored for histone methylation. Lysine methyltransferases catalyze the transfer of a methyl group from SAM to a ε-amino group of lysine, whereas arginine methyltransferases catalyze the transfer of a methyl group from SAM to arginine’s ω-amino group. Histone demethylases have the opposite effect to histone methylases, both can activate or repress the transcriptional activity (Bannister et al., 2002). For example, methylation of histone H3 at K9 and K36 may negatively affect the promoter region while a positive one in the coding region (Kouzarides, 2007). Additionally, decreased levels of acetylation of histones H3 and H4 and elevated levels of DNA methyltransferases are usually found in prostate cancer cells (Baumgart and Haendler, 2017).

Histone phosphorylation is highly versatile and occurs predominantly at serine, threonine, and tyrosine residues. Phosphorylation results from the transfer of a phosphate group from ATP to the hydroxyl group of the amino acid side chain that is catalyzed by histone kinases (Xhemalce et al., 2011).

A recent study also revealed that lactate, produced by the incomplete oxidation of glucose through the Warburg effect in cancer cells, can regulate gene expression in macrophages by functioning as a new histone modification, i.e., lactylation. Excessive lactate production, i.e., Warburg effect benefits cancer in number of ways-promotes metastasis, angiogenesis, activation of T cells, polarization of macrophages. Now it is well documented that lactic acid also contributed in epigenetic modifications by adding the lactyl group on the ε-amino group of a lysine residue (Zhang et al., 2019).

In addition, there are diverse sets of posttranslational histone modifications that include deamination, ADP ribosylation, ubiquitylation, and sumoylation but are beyond the scope of this review.

In the last two decades, several dietary compounds have been confirmed to play a substantial role in the reversal of histone onco-modification and a few of the most important of them are discussed in detail below.

In prostate cancer cells, apigenin induced a decrease in HDAC activity, downregulated HDAC1 and 3 expression, and increased acetylation of histones H3 and H4. In vivo studies reveled that apigenin treatment reduced tumor growth and a significant decrease in HDAC activity that correlated with increased levels of p21/waf1and Bax protein along with a reduction in protein levels of bcl2 that favored apoptosis in tumor cells of the mice (Pandey et al., 2012). Another in vivo study on the breast cancer cell line of athymic nude mice revealed a decrease in HDAC activity on treatment with apigenin in a dose-dependent manner. Acetylation of histone H3 was shown to increase after treatment with apigenin correlated with transcriptional activation of p21 ^WAF1/CIP1 gene (Tseng et al., 2017). Apigenin treatment lowered the protein expression levels of HDAC1, 3, 4, 5, 6, and 8 in the mouse skin cancer cell line in a dose-dependent manner (Paredes-Gonzalez et al., 2014).

Curcumin treatment resulted in inhibition of cell proliferation in Raji cells of B-NHL cancer. The protein expression levels of HDAC1, 3, and 8 were also found to be downregulated and acetylation of H4 histone increased after treatment with curcumin in a dose- and time-dependent manner (Liu et al., 2005). In HeLa nuclear extracts, curcumin decreases the HDAC activity. Docking studies suggested curcumin as a potent inhibitor of HDAC8 than its carboxylic acid-derived pharmacological counterparts (Bora-Tatar et al., 2009). In human hepatoma Hep3B cells, curcumin induced a decrease in H3 and H4 histone acetylation. Further in vitro studies showed curcumin treatment decreased core histone acetylation catalyzed by HAT extracted from Hep3B cancer cell line that suggested the role of HAT in curcumin-induced histone hypoacetylation (Kang et al., 2005).

In a recent study, demethylzeylasteral treatment promoted decrease in tumor progression in liver stem cells by inhibiting H3 lactylation (H3K9la and H3K56la) (Pan et al., 2022).

Green tea polyphenol (GTP) treatment decreased a maximum of 43% HDAC activity in a time-dependent manner in prostate cancer cells, which was similar to Trichostatin A (TSA) that caused 45% inhibition in 24 h. Furthermore, a decrease in protein expression of HDAC1 and 3 was also observed. GTP treatment decreased the mRNA levels of HDAC1, 2, and 3 in a gradual time course, whereas no such changes were observed with TSA. Exposure to GTP further resulted in a 22-fold and 2.2-fold increase in H3 and H4 acetylation, respectively, in a gradual-time course (Pandey et al., 2010). EGCG treatment significantly reduced HDAC activity in skin cancer cell line A431. Acetylation and methylation levels of H3K9 were found to be increased and decreased, respectively, when treated with EGCG. Furthermore, acetylation of H3K4 and H4K5, 12, and 16 were shown to be increased after EGCG treatment, thus reactivating tumor suppressor genes (Nandakumar et al., 2011). In prostate cancer cells, GTP and its major constituent EGCG induced treatment caused a substantial decrease in the expression and activity of HDAC 1, 2, 3, and 8. On further investigation, EGCG acetylated the p53 gene at K373 and K382, which was found to be diminished when the EGCG treatment was withdrawn after a certain time period (Thakur et al., 2012).

Genistein treatment increased acetylation at H3, H4, and H3 dimethylated at K4 near the transcription start sites of tumor suppressor genes p21 and p16 in prostate cancer cell lines. ChIP analysis revealed an elevation in HAT activity, suggesting an increase in transcription level and gene activation after treatment with genistein (Majid et al., 2008). Genistein, eqoul, and AglyMax induced ER-mediated core histone acetylation via modulating the activity of HATs, and daidzein stimulated Erβ mediated histone acetylation (Hong et al., 2004).

Triple-negative breast cancer is considered the most aggressive subtype of breast cancer. An in vitro study on the effect of indole-3-carbinol on HCC70 triple-negative breast cancer cell lines has shown to inhibit the overall HDAC activity (Nouriemamzaden et al., 2020).

PEITC treatment of LNCaP prostate cancer cell line significantly reduced the protein levels of HDAC1, 2, 4, and 6 that correlated with promoter demethylation and activation of a tumor suppressor gene, RASSF1A (Boyanapalli et al., 2016). Histone hypoacetylation due to excessive HDAC activity is one of the hallmarks of leukemia. Mononuclear extracts from the bone marrow of acute myeloid leukemia patients showed limited or no H3 and H4 histone acetylation. However, after treatment with phenylhexyl isothiocyanate (PHI), there was a significant elevation in H3 and H4 histone acetylation compared to the control cultures (Xiao et al., 2010).

In HL-60 leukemia cancer cell lines, quercetin treatment induced FasL expression that triggered extrinsic apoptotic pathway, protein activation and conformational changes, and activation of ERK and JNK signaling pathways. Furthermore, H3 acetylation was found to be increased in quercetin treated HL-60 cells, and upregulated HAT activity and downregulated HDAC activity together resulted in stimulation of FasL expression (Lee et al., 2011). Leukemia cancer cell lines when treated with quercetin showed an increase in global histone acetylation of H3 and H4 histones. Promoter regions of proapoptotic genes experienced a three-to ten-fold increase in H3 and H4 acetylation in HL-60 and U937 cancer cells. In vitro and in vivo studies of two human xenograft myeloid leukemia models exhibited a decrease in HDAC1 and 2 activity after treatment with quercetin (Alvarez et al., 2018). Quercetin treatment significantly reduced the HDAC activity in a dose-dependent manner and HMT activity at H3 histone, which may methylate and trimethylate the ninth lysine residue in HeLa cancer cell lines. Molecular docking results of quercetin reported a decline in HDAC activity, suggesting that quercetin can competitively inhibit HDAC2, HDAC4, HDAC7, and HDAC8 by binding to the catalytic residue sites (Kedhari Sundaram et al., 2019).

In breast cancer cell lines, resveratrol decreases the protein levels of arginine methyltransferase PRMT5, lysine methyltransferase EZH2, and lysine deacetylase KDAC in a dose- and time-dependent manner that correlated with an increase in protein levels of BRAC1, p21, and p53 genes. After treatment with resveratrol, near to the proximity of the transcription start site of the mentioned genes, the levels of H4R3me2s and H3K27me3 were found to be decreased while that of H3K9ac and H3K27ac increased (Chatterjee et al., 2019). In human carcinoma cell line, resveratrol treatment increase the protein levels of acH3K9, acH3K14, acH3K12, acH4K5, and acH4K16, suggesting anti-tumor effects of resveratrol (Dai et al., 2020).

In human malignant melanoma cells, sulforaphane, decreases the protein expression levels of HDAC1, 2, 4, and 6. Sulforaphane also decreases the total HDAC activity and protein expression levels of CBP, CBP/p300, and PCAF. Furthermore, the protein expression levels of acH3K9, 14, and 27, and acH3K8 and 12 were significantly reduced after treatment with sulforaphane. The study also revealed a decrease HMT activity of SET7/9, further affecting the methylation at K9, 36, and 79 when treated with sulforaphane (Mitsiogianni et al., 2020). TERT (Telomerase Reverse Transcriptase) is associated with processes such as cell proliferation, senescence, cell differentiation, etc., and any alteration in it contributes to immortality and carcinogenesis. Sulforaphane treatment suppressed HDAC activity in prostate cancer cells and induced an increase in pan-acetylation of H3 and H4 histones of the hTERT promoter (Abbas et al., 2015).

Furthermore, the histone modulation activity of various phytocompounds like diallyl disulfide, garcinol, ginsenoside Rh2, phenyl hexyl isothiocyanate, rosmarinic acid, etc., in distinct cancer types is mentioned in Table 3.

Based on the studies mentioned above, it is evident that a wide range of phytocompounds (apigenin, curcumin, sulforaphane, resveratrol, genistein, quercetin, etc.) possess the ability to target major histone modifications that regulate gene expression of apoptosis, cell proliferation and inflammatory pathways (extensively discussed in section 6), all of which, when dysregulated can lead to carcinogenesis.

Any alterations during the biogenesis of miRNA or mutation of the factors can have profound implications. A category of miRNAs, termed as epi-miRNAs (epi-miRs), has recently been discovered to modulate the expression of genes encoding epigenetic reader proteins (Dai et al., 2014). Aberrant modulation of epi-miRs can induce epigenetic silencing of tumor suppressor genes or activation of oncogenes, resulting in carcinogenesis. MicroRNAs have been classically categorized as two distinct epi-miRs, namely, OncomiRs and tumor-suppressor miRs that play distinctive roles in tumorigenesis. OncomiRs are generally upregulated, resulting in enhanced cancer cell proliferation and metastasis, whereas tumor-suppressor miRs are downregulated leading to carcinogenesis (Svoronos et al., 2016; Sadakierska-Chudy, 2020). Phytocompounds that are known to alter the epi-miRNAs is the entire effect of the each phytocomponents is supported by a single publication are listed in Table 4.

A significant proportion of studies have demonstrated the potential role of phytocompounds in the regulation of epi-miRs in carcinogenesis. For instance, the apigenin-treated glioma cancer cell line U87 exhibited increased miR-16 expression, decreased BCL2 protein expression, and decreased expression of the MMP-9 gene. Anti-miR-16 transfection inhibited apigenin-induced miR-16 gene expression. Furthermore, anti-miR-16 transfection inhibited apigenin-induced miR-16 gene expression, increased BCL2 protein expression and NF-κB/MMP-9 levels (Chen et al., 2016).

Curcumin induced upregulation of miR-99a in retinoblastoma cancer cell line, SO-Rb50, and Y-79. When the cells were transfected with miR-99a inhibitor, the miR-99a expression decreased that correlated with anti-tumor activity of curcumin through enhancement of miR-99a expression. Phosphorylation levels of JAK1, STAT1, and STAT3 were significantly reduced when treated with curcumin, although no such effect was observed when miR-99a was knocked down (Li et al., 2018). Curcumin-treated breast cancer cell line MCF-10F resulted in decreased gene transcript and protein levels of Axl, Slug, CD24, and Rho-A, which are associated with epithelial-mesenchymal transition (EMT). An increased expression of miR-200a, let-7b, and miR-34a was found in the MCF-10F cancer cell line, while only miR-34a expression increased in the MDA-MB-231 cancer cell line after exposure to curcumin. An increase in expression of the examined genes occurred after the knockdown of miR-34a, while the genes were found downregulated when treated with curcumin and transfected with anti-miR-34a. The invasive and migrating capabilities of MCF-10F decreased when cells were transfected with anti-miR-34a and treated with curcumin (Gallardo et al., 2020).

Ellagitannin treated hepatocarcinoma cells showed a decrease in cell proliferation. The treatment further downregulated and upregulated the expression of various mi-RNAs (Table 4) (Wen et al., 2009).

Hepatocarcinoma cell line HepG2 exhibited decreased growth when treated with EGCG in a dose-dependent manner. miR-18a, miR-34b, miR-193b, miR-222, and miR-342 were found to be downregulated, while miR-16, miR-221, and let-7b were found to be upregulated after treatment with EGCG. Bcl-2 expression was suppressed after transfection with miR-16. Furthermore, transfection with miR-16 enhanced the activity of EGCG in Bcl-2 suppression and induction of apoptosis (Tsang and Kwok, 2010). Nasopharyngeal cancer cell line CNE2 was treated with EGCG where 32 miRNAs exhibited > 2-fold changes that have been shown to modulate cancer development, out of which 29 miRNAs were found to be upregulated and 1 miRNA was downregulated in a dose-dependent manner (Li et al., 2017).

Genistein-treated prostate cancer cell lines, exhibited an increase in miR-574-3p expression compared to the control. Transfection with pre-miR-574-3p miRNA precursors into PCa cell lines led to a significant increase in miR-574-3p expression and decreased cell invasion. In an in vivo study, the transfection of DU145 cells with miR-574-3p subcutaneously into nude mice resulted in tumor suppression due to overexpression of miR-574-3p (Chiyomaru et al., 2013). A significant increase in miR-145 expression was observed in genistein-treated retinoblastoma cancer cell line (Y79). Genistein treatment also reduced cancer cell proliferation and induced apoptosis. Y79 cells transfected with miR-145 specific siRNA resulted in the restoration of colony formation capacity and suppression of cell apoptosis that was induced due to genistein treatment. In silico studies suggested ABCE1 gene to be a potential target of miR-145. Furthermore, an in vivo study on the xenograft nude mice model revealed the suppression of tumor growth in Y79 cells administered with genistein (Wei et al., 2017).

Treatment with lycopene induced upregulation of miR-let-7f-1 in a dose and time-dependent manner in prostate cancer cells. Furthermore, transfection with miR mimics led to inhibition of cell proliferation and apoptosis induction (Li et al., 2016).

PEITC treated prostate cancer cell lines exhibited an increase in the expression of miR-194. Furthermore, the expression of the two matrix metalloproteinase, MMP2 and MMP9, which significantly contributes to tumor progression in terms of migration, invasion, and metastasis, decreased when treated with PEITC. An in silico study revealed BMP1 is a potential target of miR-194 and its inhibition tends to downregulate MMP2 and MMP9 levels (Zhang et al., 2016).

Quercetin-treated oral cancer cells exhibited an increase in miR-16 expression. Cell viability, migration, and invasive capabilities of oral cancer cells were found to be repressed when transfected with miR-16. HomeboxA10 (HOXA10) was found to be targeted by miR-16 after the bioinformatics analysis of the binding sites of HOXA10 and miR-16. HOXA10 is generally involved in the proliferation, invasion, and migration of cancer cells and is one of the potential biomarkers in oral cancer. Overexpressed miR-16 downregulated the protein levels of HOXA10, while the opposite was observed in miR-16 knockdown cells (Zhao et al., 2019). In breast cancer cells, miR-146a expression increased after treatment with quercetin in a dose-dependent manner. Furthermore, growth of the cells was inhibited after transfection with miR-146a mimic and treatment with quercetin. A substantial elevation in the expression of Bax and cleaved caspases was observed when transfected with miR-146a. Quercetin treatment for 8 weeks increased miR-146a expression and reduced tumor growth in a nude mouse orthotopic xenograft model (Tao et al., 2015).

Colorectal cancer cell line HCT-116 exhibited a decrease in cell viability in a dose-and-time-dependent manner when treated with resveratrol. HCT-116 cells transfected with LNA miR inhibitor showed a dramatic decline in miR-200c expression compared with the un-transfected and scrambled groups. After treatment with resveratrol, miR-200c expression increased significantly in both transfected and un-transfected cells. Resveratrol treatment reduced the mRNA and protein expression of vimentin and ZEB1, while that of E-cadherin increased in both groups that correlated with EMT induction (Karimi Dermani et al., 2017).

Rosmarinic acid decreased cell viability, cell proliferation, invasion, and migration and suppressed EMT while promoting apoptosis in pancreatic cancer cell lines. Further treatment resulted in increased miR-506 levels that correlated with suppression of MMP2 and MMP16 proteins. The xenograft mouse model also exhibited a reduction in tumor growth after treatment with rosmarinic acid (Han et al., 2019).

Sulforaphane-treated pancreatic cancer cell lines showed a substantial increase in miR135b-5p. Cells transfected with liposomes of miR-135b-5p mimics exhibited overexpression of miR-135b-3p that resulted in reduced cell viability, migration, and colony-forming capacity. In silico analysis revealed RASAL2 to be a potential target of miR-135b-3p. Furthermore, an in vivo studies on tumor xenografts, where BxPC-3 cells were transfected with miR-135b-3p mimics, resulted in decreased tumor size that correlated with overexpression of miR-135b-3p and RASAL2 (Yin et al., 2019). In colorectal cancer cell, sulforaphane treatment inhibited oncogenic miR-21, decreased cell viability, induced apoptosis, and downregulated the expression of hTERT (Martin et al., 2017).

In human glioblastoma cells, miR-21 levels were increased that has been shown to target a positive regulator of apoptosis, the PDCD4 gene. Ursolic acid treatment decreased cell proliferation and induced apoptosis while suppressing the levels of miR-21 that eventually led to enhanced expression of PDCD4 (Wang et al., 2012).

All these studies discuss the therapeutic effect of phytocompounds targeting epi-miRs that either decreases or increases miRNA level to eventually reduce tumorigenesis. An elaborate list of phytocompounds modulating miRNA in specific cancer cell types is provided in Table 4.

Autophagy plays a dual role in cancer by promoting tumorigenesis or suppressing tumor progression. To satisfy the high metabolic requirements of proliferating tumor cells, autophagy recycles the cells’ intracellular constituents to supply nutrients, while suppression or inhibition of autophagy genes may result in cancer cell death. Autophagy also promotes inflammation in tumor cells, which eventually results in tumor progression (Yun and Lee, 2018). Post-translational modifications like acetylation, phosphorylation, ubiquitination, nitrosylation can influence autophagy by regulating the activity of ATG proteins and the expression of genes involved in autophagy (Botti-Millet et al., 2016). As described above, many studies have shown that deregulation of ATG genes through different epigenetic modulations can cause tumor progression. For instance, curcumin treatment inhibited DNMT1 and DNMT3B expression in prostate cancer cells that resulted in promoter hypomethylation of miR-143 and miR-145. This restoration of miRNAs further downregulated ATG2B expression, thus inhibiting autophagy (Liu et al., 2017).

Dysregulation of apoptosis is one of the hallmarks of cancer. Cancer cells tend to survive longer and accumulate mutations due to deregulation of apoptosis over a period of time. Furthermore, deviations from normal apoptotic pathways can enhance the invasiveness of cancer cells and promote angiogenesis. In most cancer cells, BCL-2 is generally overexpressed while the function of caspases is found to be disabled (Pfeffer and Singh, 2018). As mentioned above, emerging studies have shown that phytocompounds can correct epigenetic modulations that interfere with apoptotic pathways that result in cancer progression.

Excessive aggregation of reactive oxygen species (ROS) has been observed in cancer. ROS is involved in inflammation, cell transformation, tumor cell survival, proliferation, invasion, angiogenesis, and metastasis, mediated through transcription factors such as NF-κB, AP-1, STAT3, etc. (Gupta et al., 2012; Prasad et al., 2017). Furthermore, the overexpression of MMPs can be correlated with enhanced invasiveness and angiogenesis in distinct cancer types (Reunanen and Kähäri, 2013). Besides this, ROS can also regulate the expression of multiple tumor suppressor genes like p53, Nrf2, PTEN, and Rb (Gupta et al., 2012). Nrf2 plays a crucial role in homeostasis maintenance and regulation of genes that produce anti-inflammatory and anti-cancer effects (Wu et al., 2019). Additionally, it is evident from the studies mentioned that abnormal epigenetic modulation can alter the function and activity of transcription factors and genes involved in the production of ROS in cancer. However, distinct phytocompounds (curcumin, resveratrol, berberine, luteolin, etc.) as mentioned above, possess the ability to reverse the activity of all these transcription factors and genes involved in the accumulation of ROS back to normal, which have been implicated in abnormal epigenetic modulation.

Therefore, it is evident from all these studies and observations that autophagy, apoptosis, inflammation, and oxidative stress play a crucial role in cancer. This warrants additional studies to understand the underlying mechanisms of genes, transcription factors, and pathways implicated in cancer. Furthermore, these implications can also be used as biomarkers in the diagnosis of distinct cancer types.