DNA methylation is one of the widely studied epigenetic mechanisms in cancer etiopathogenesis. Aberrant methylation leads to DNA hypermethylation or hypomethylation. In DNA hypermethylation, the process of methylation occurs at the cytosine bases present in the promoter region of genes by a group of enzymes called DNA methyltransferases (DNMTs), including DNMT1, DNMT3a, and DNMT3b (Jones and Baylin, 2002). These enzymes convert cytosine residues to 5-methylcytosine eventually leading to decreased gene expression via transcriptional suppression (Fan et al., 2012; Li et al., 2012). On the contrary, DNA hypomethylation indicates overall decrease in the methylation levels as compared to normal cells, and affects the intergenic and intronic regions of the DNA, resulting in chromosomal instability and increased mutation activities (Wilson et al., 2007). The global hypomethylation with hypermethylation of specific gene promoters has already been reported by various studies on cancer (Kurkjian et al., 2008). Thus, inappropriate DNA methylation may lead to altered expression of tumor suppressor genes (deregulation) and/or oncogenes (upregulation) in cancer cells (Kulis and Esteller, 2010). In fact, differences in methylation patterns exist within CpG islands of ∼70% of all mammalian promoters, which have been known to play an important role in transcriptional and post-transcriptional regulation (Robertson, 2005; Tost, 2009). In addition, the introduction of high throughput sequencing has confirmed that 5–10% of abnormally methylated CpG promoter islands are present in various cancer genomes. Also, the hypermethylation of CpG islands in several promoters influences the expression of various noncoding RNAs (ncRNA) as well as messenger RNAs (mRNA), which are known to have a role in cancer progression (Baylin and Jones, 2011). Even, the whole genome sequencing data in several cancers have shown that various somatic mutations exhibit in numerous epigenetic regulators (Forbes et al., 2017).

A less studied epigenetic process is RNA methylation. It is about seven times greater than DNA methylation. These modifications result in mRNA localization and transcript degradation (Zaccara et al., 2019). With the advent of next generation sequencing and the discovery of RNA methylation-related proteins, it is easy to comprehend that methyl modifications at mRNA level may affect the cellular processes resulting in human diseases. Presently, over 150 different RNA modifications have been observed, of which the N⁶-methyladenosine (m⁶A) modification is the most abundant and it is recognized by RNA binding proteins that affect many characteristics of mRNA function (Schwartz et al., 2014; Linder et al., 2015). Similar to modifications at the DNA methylation level, alterations at RNA level affect the epigenetic regulation of gene expression (Figure 1).

We are already familiar with the chromatin structure which involves wrapping of DNA on histone octamer -2 subunits each of H2A, H2B, H3 and H4 proteins joined together by H1 proteins. Histone modification takes place at the amino-terminal tail of these histones via the process of acetylation, methylation, phosphorylation, ADP-ribosylation, or ubiquitination. Several enzymes are known to catalyse the above-mentioned processes. The addition of acetyl, methyl, phosphate group etc. to histone amino-terminal tail is performed by histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone kinases. These epigenetic marks are known as writers and act as transcriptional co-activators. On the contrary, erasers [histone deacetylases (HDACs), histone demethylases (HDMs), phosphatases] function as transcriptional co-repressors by removing these groups from histone end (Li et al., 2020). All these enzymes are involved in the simultaneous opening and closing of chromatin structure, which is necessary for gene expression to occur (Figure 1). Aberrations in these enzymes may lead to altered gene transcription and post-transcriptional modifications, thereby resulting in cancer.

The DNA nucleosome interactions can be modified (histone ejection, removal and incorporation) through chromatin remodelling complexes by ATP hydrolysis. These chromatin-remodelling complexes can be classified into switching defective/sucrose nonfermenting (SWI/SNF), chromodomain-helicase DNA-binding protein (CHD), imitation SWI (ISWI), and INOsitol requiring mutant 80 (INO80) complexes. The catalytic subunit of these complexes performs DNA translocation along with the histone core of the nucleosome (Clapier et al., 2017).

The SWI/SNF complexes are one of the most widely studied ATP dependent chromatin remodelling complexes. They are found to be mutated in 25% of human cancers (Mittal and Roberts, 2020) and are playing an essential role in chromatin remodelling by positioning nucleosomes. Their catalytic activity is known to be associated with SMARCA4/2 proteins. Numerous studies also suggest that SWI/SNF complexes are involved in the regulation of cell progression, cell motility, and nuclear hormone signalling (Wilson and Roberts, 2011). The SWI/SNF complex was found to be altered in 33–42% of pancreatic cancer cases by whole-exome sequencing studies (Shain et al., 2012; Witkiewicz et al., 2015).

The next important complex is ISWI which mobilizes nucleosomes by helping the transcription factors to bind a nucleosome-free DNA. Unlike SWI/SNF complex, ISWI is held to nucleosomes by a SANT and a SLIDE domain (Grüne et al., 2003). As reported in the literature, ISWI complexes have a key role in DNA repair and recombination (Aydin et al., 2014). In humans, two ISWI subunits namely sucrose nonfermenting 2L (SNF2L) and sucrose nonfermenting 2H (SNF2H) ATPases are identified. It has been noticed that SNF2H suppressed the oncogene ras in human cells (Andersen et al., 2006). A tissue microarray study on 78 paraffin wax-embedded prostatic tissues observed a significant increase in ISWI (SNF2L and SNF2H) proteins in prostatic intraepithelial neoplasia and prostate adenocarcinoma (Mohamed et al., 2007). To date, no clinical trials have been performed to unravel the potential of these small molecules as epigenetic biomarkers in cancer therapies.

Prostate cancer is the second most common cancer (14.8%) in men and the fourth leading cause of cancer related death (6.6%) (Sung et al., 2021), globally. Prostate cancer is quite heterogenous and lethal disease at clinical level, which makes it impervious not only to diagnose it early but also for evaluating the threat that a given prostate cancer bears to its host (Jain et al., 2014). Therefore, further studies are required to develop epigenetic biomarkers to meet these goals. In 95% of prostate cancer patients, higher expression of PCA3 and ncRNA have extensively been reported in blood samples. Commercially available PROGENSA™, prostate cancer biomarker (Durand et al., 2011) quantifies PCA3 expression ratio normalized as input control for prostate specific antigen (PSA) mRNA. For early detection of prostate cancer by semi non-invasive method, PCA3 testing may be useful, thus also avoiding unnecessary prostate biopsy. The most promising prostate cancer epigenetic biomarkers are DNA methylation and glutathione S-transferase pi gene (GSTP1) promoter hypermethylation (Maldonado et al., 2014).

Few studies have reported a correlation of promoter methylation at the methylguanine-DNA methyltransferase (MGMT) gene with favorable treatment outcomes in glioblastoma patients treated with temozolamide, suggesting its possibility to be used as an epigenetic biomarker (Donson et al., 2007; Rosas-Alonso et al., 2021; Kim et al., 2022).

Studies have shown that high levels of hypermethylated DNA exists in colorectal cancer which leads to genomic instability (Toyota et al., 1999). The methylation status of five genes- CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS126 may identify CpG island methylator phenotype (CIMP) positive colon cancers, which are characterized by high incidence of p16 and THBS1 methylation and frequent KRAS and BRAF mutations (Lao and Grady, 2011; Zhang et al., 2021). One of our published studies observed that RASSF1A, FHIT and MGMT gene methylation patterns may be used as markers in diagnosing colorectal cancer (Sinha et al., 2013).

A recent epigenomic study has shown differential methylation patterns in several genes which may account for esophageal cancer development and in future can be realised as diagnostic biomarkers (Lin et al., 2018). An Indian study observed promoter methylation in 52% of histopathologically confirmed tumor tissues and the methylation frequency increased with higher histological grades of the cancer (p = 0.0001) (Salam et al., 2009).

In 2021 (Sung et al., 2021), the incidence rate of bladder cancer was 3.3%, and the mortality rate of 2.0% globally. At present no accurate diagnostic or prognostic biomarkers are commercially available. Some biomarkers representing higher sensitivity than cytology (Letelier et al., 2012) have been reported based on methylation. As per some studies, based on genome-wide characterization, bladder cancer cells demonstrated that VIM, GDF15, and TMEFF2 show 94% sensitivity and 100% specificity in urine samples (Costa et al., 2010). The data of other epigenetic alterations like histone modification in bladder cancer is infrequent.

Several studies have suggested alterations in histone-modifying enzymes like enhancer of zeste homolog 2(EZH2). This enzyme is encoded by EZH2 gene, which participates in histone-methylation and transcriptional repression. EZH2 has significantly reduced expression of histone in breast cancer (Yomtoubian et al., 2020). Another one is Protein Arginine Methyltransferase (PRMT1). It is also a histone modifying enzyme which plays an important role in the epithelial-to-mesenchymal transformation (EMT) of breast cancer cells (Mathioudaki et al., 2011) in the development of cetuximab sensitivity in triple-negative breast cancer (TNBC) cell lines (Gurdal et al., 2019) with high grade malignancy and poor prognosis (Bianchini et al., 2016). The role of SETD7 (SET Domain Containing 7), lysine methyl transferase in post translational modification of non-histone protein and having prognostic as well as negative effects with tumorigenesis and poor prognosis in patients (Huang et al., 2017) with the expression of lysine methyltransferase SETD7 has been suggested. It is a potential promoter of the antioxidant pathway balancing the cytotoxic effect of oxidative stress. Further validation, for histone modification-based biomarkers is still required.

Stirazaker et al., 2015 divided TNBCs into different epigenetics groups viz. high, intermediate, and low-risk groups based on epigenetic subtypes and the methylated region that is correlated with the progression of the disease. One of the recent studies has also confirmed a correlation between shorter periods of reduction in analysed TNBC-samples (Stirzaker et al., 2015) and hypermethylation of gene regions. Hypermethylation provides explanations and evidence for clinical threat and helps in treatment planning in patients having a higher risk of recurrence.

The worldwide incidence and mortality rates of ovarian cancer in the year 2021 were 1.1% and 2.3%, respectively (Sung et al., 2021). Histone modifications by acetylation with aberrant tubulin protein expression, reduction of PACE3 expression, silencing of survivin (BIRC5), upregulation of pRb tumor suppressor gene and CDKN1 (Cyclin-dependent Kinase) were reported in ovarian tumor formation. Furthermore, the overexpression of Histone Deacetylase Enzymes HDAC3, and loss of H3K27me3 (an epigenetic modification of DNA histone protein H3) was reported to be associated with prognosis (Li et al., 2021) and higher stages of tumor in ovarian cancer. H3K4me3 plays an important role in the transcriptional repression of tumor necrosis factor TNFRSF11B and upregulate the H3K27me3 (Chapman-Rothe et al., 2013). The loss of RNF20 (Ring Finger Protein 20) and H2Bub1 (H2B monoubiquitination) to the progression of ovarian tumors by chromatin remodelling has been reported by a very recent study (Hooda et al., 2019). Tang et al. (2018) revealed that AMPK (Activated Protein Kinase) moderate the repression of H3K27me3 after treatment with metformin and expressed its usefulness in the treatment of ovarian cancer cases. A study also reported that EZH2 facilitates TIMP2 (Tissue Inhibitor of Metalloproteinase 2) and ADP-Ribosylarginine hydrolase 1 (ARH1) by DNA methylation and H3K27me3, which leads to ovarian cancer metastasis. Their inhibitors could thus be used as potential epigenetic biomarkers for the early detection and diagnosis of cancer after proper clinical studies and validation of the same.

Research has recognized the role of epigenetics in developing drug resistance thereby affecting cancer treatment. Cacan et al. (2016) reported that the loss of apoptosis antigen 1 expression impacts drug resistance, which is mediated by histone deacetylase 1 (HDAC1) in chemoresistant ovarian cancer cells (Cacan, 2016). Using ChIP-sequencing, Curry et al. (2018) identified H3K27me3 and H3K4me3 methyltransferases in the promoter region in tumor cases which were acquired resistance for pre and post platinum and showed that these genes are involved in epigenetic silencing during chemotherapies and are prone to hypermethylation thus providing novel awareness to prevent disclosure of drug resistance (Curry et al., 2018).

A recent study has described hypomethylation of developmental genes MSX1, DAXX and TMEM88. mRNA expression of these developmental genes is associated with platinum resistance and inversely correlated with promoter methylation in ovarian cancer patients by treatment with Guadecitabine (DNA methyl transferase inhibitor) and cisplatin (Bonito et al., 2016; de Leon et al., 2016).

DNA methylation regulates epithelial mesenchymal transition (EMT) by lncRNA (HOTAIR) and it is a sign of resistance to carboplatin (Singh et al., 2019). A study has also described how DNA methylation targeted genome scale strategies could prevent the formation of tumors, for example Guadecitabine facilitated inducing hypomethylation, activates tumor suppressor genes and affects metabolic and immune responses to contributing platinum drug desensitization in ovarian cancer. It may help in improving of patients survival outcomes with ovarian cancer (Fang et al., 2018). An epigenetic study described that the methylation of Zinc Finger protein 671 (ZNF671) can serve as a prognosticator for the early relapse of ovarian tumorigenesis and correlates with disease aggressiveness and progression (Zhang et al., 2019). Epigenetic inhibitors used for combinational therapies, would possibly be most effective by repair of pathways associated with drug response for chemo-desensitization of resistant tumors and would consequently implicate improved survival outcomes as well as personalized treatment for various cancers.