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DNA methylation is one of the most important epigenetic modifications next to acetylation or histone modifications, as it has a role in the homeostatic control of the cell and is strongly involved in the control of genome expression. DNA methylation, which is catalyzed by DNA methyltransferases (DNMTs), is one of the primary epigenetic mechanisms that control cell proliferation, apoptosis, differentiation, cell cycle, and transformation in eukaryotes. Hypomethylation and hypermethylation result in the activation or repression of genes and in a normal cell there is a strict balance between these processes. Abnormal DNA methylation is a well-known feature of cancer development and progression and can turn normal stem cells into cancer stem cells. Studies clearly show that DNA methylation regulates gene transcription functions in cancer pathogenesis. In cancer cells, DNA methylation patterns are largely modified, and therefore, methylation is used to distinguish cancer cells from normal, healthy cells. However, the mechanisms underlying changes in DNA methylation remain unexplored. However, it is known that oxidative stress (OS) is a key mechanism of carcinogenesis, and DNA methylation of genes that are active at OS may play a role in cancer development. Studies also show that DNA methylation is mediated by long noncoding RNA (lncRNA) under both physiological and pathological conditions. How cell-specific DNA methylation patterns are established or disrupted is a key question in developmental biology and cancer epigenetics.
*Address all correspondence to: evelin@man.poznan.pl
1. Introduction
Epigenetics in the etiology of cancer progression is of major importance. Epigenetic changes, such as histone modifications, DNA methylation, chromatin remodeling, nucleosome positioning, regulation by noncoding RNAs and precisely microRNAs, play a significant role in the cancerogenesis of different cancer types. Epigenetic processes result in altered levels of gene transcriptional activity without directly affecting the primary DNA nucleotide sequence. Changes in DNA methylation patterns together with specific histone modifications (methylations, acetylations, deacetylations, etc.) contribute to a transcriptionally inactive chromatin state. In cancer cells, DNA methylation patterns are modified, and these differences are used in the diagnostic process to distinguish cancer cells from normal tissues [1]. Aberrations of normal DNA methylation patterns are observed in many cancers and are associated with chromatin alterations, changes in gene expression, and genome instability, making the study of DNA methylation crucial to understanding cancer biology and evolution and biomarker development [2]. Epigenetic clocks, assessed by DNA methylation levels, are among the most commonly used biological age markers in cancer research [3], as DNA methylation occurs early in tumorigenesis and often precedes somatic cell mutation [4].
DNA methylation, as an epigenetic mechanism, occurs through the addition of a methyl group at the 5′ position of the pyrimidine ring of cytosines and plays an important role in cellular function, particularly in the transcriptional regulation of embryonic and adult stem cells. Genomewide analysis revealed different patterns of DNA methylation in different cell types, developmental stages, and in response to different stimuli. Abnormal DNA methylation patterns—hypomethylation or hypermethylation—cause gene expression or inhibition, lead to genome instability and DNA breakage. DNA hypomethylation occurs in the intergenic regions and repetitive DNA sequences of cancer cells, while DNA hypermethylation occurs at CpG islands in gene promoters. DNA hypermethylation is mediated by DNA methyltransferases, DNMT3a, 3b, and DNMT1, during de novo methylation (Figure 1). There is a tight balance between the regulation of gene activation or repression in normal cellular activity. When this balance is disrupted, for example, by oxidative stress, anomalous states arise. Hypomethylation promotes genomic instability, causing erroneous aggregation of chromosomes during cell division and unwanted activation of transposable elements in the genome, leading to further genetic damage [5, 6]. DNA hypomethylation can lead to activation of oncogenes (e.g. mesothelin, proopiomelanocortin gene, S100A4, and claudin4) and cancer progression, while DNA hypermethylation can lead to inactivation of tumor-suppressor genes, resulting in deregulated cell growth or altered response to anticancer therapies [7, 8]. DNA hypermethylation inactivates tumor-suppressor genes such as adenomatous polyposis coli (APC), retinoblastoma (Rb), or BRCA1, as well as others involved in DNA repair such as MGMT, apoptosis (DAPK) or antioxidation (GSTP1) [8, 9]. Abnormal methylation turns normal stem cells into cancer stem cells (CSCs). CSCs are small populations of cancer cells that exhibit unique properties such as self-regeneration, resistance to chemotherapy, and high metastatic capacity [10].
Figure 1.
DNA methylation and DNA methyltransferases (DNMT) function. DNA hypomethylation occurs in the intergenic regions of cancer cells, while DNA hypermethylation at CpG islands occurs in gene promoters. DNA methyltransferases: DNMT 1, DNMT3a, and DNMT3b play a major role in the methylation process.
2.1 Effect of DNA methylation on cancer progression
Epigenetic changes, particularly changes in DNA methylation, are much more common than the frequency of genetic changes in the vast majority of cancer types. This is significant and demonstrates the importance of epigenetics both when used as a diagnostic and therapeutic tool.
The expression of DNA methyltransferases (DNMTs), which are responsible for carrying the methyl group during methylation, gradually increases with the transformation process from normal tissue to precancerous lesions and becomes overexpressed in cancer cells. In humans, during early embryogenesis, DNMT1, DNMT3a, and DNMT3b are the enzymes that establish methylation patterns. Abnormal DNA methylation—hypermethylation and hypomethylation—is closely associated with cancer tumor development. DNMT overexpression leads to hypermethylation of gene promoters, DNA methylation of the tissue-specific gene, thus hypermethylation of the CpG island can lead to tumor development (Figure 2). The most common genes with hypomethylation are oncogenes whose expression is upregulated in tumor progression. Therefore, increasing evidence has revealed specific mechanisms of methyltransferases (writer), demethylases (eraser), and DNA-binding proteins (reader) in the regulation of abnormal methylation during tumor development [4]. Demethylases remove the methyl group as an eraser, while readers are a class of proteins that are able to recognize the methylation mark by their distinct domains and induce different biological functions.
Figure 2.
Effect of DNA methylation on carcinogenesis.
Modification of DNA methylation affects a number of biological processes, such as growth, differentiation, and transformation mechanisms of eukaryotic cells. In mammals, it plays the most important role in placental and embryonic development and is essential for embryonic development. Abnormal DNA methylation can lead to many disorders in the body. DNA methylation is associated with diseases such as autoimmune diseases, neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, rheumatoid arthritis or various types of cancer. Studies have confirmed abnormal DNA methylation of fixed loci in many types of cancers, such as colon, pancreatic, breast, ovarian, esophageal, bladder, kidney, or bone cancer.
2.2 Oxidative stress in DNA methylation
Oxidative stress (OS) is the primary mechanism of cancerogenesis, and DNA methylation regulates gene transcription functions in cancer pathogenesis [11]. We speak of oxidative stress when there is excessive production of reactive oxygen species (ROS) in the cell and when the cell has a reduced antioxidant defense. A potentially mutagenic change in ROS-induced DNA damage is O6-methylguanine. Many studies have shown that its presence can inhibit the binding of DNA methyltransferases, that is, it can lead to hypomethylation by inhibiting the methylation of neighboring cytosine molecules. Alternatively, O6-methylguanine may spontaneously misuse thymine and thus contribute to DNA hypomethylation. Studies have shown that genomewide hypomethylation increases mutation rates and thus leads to genome instability. In addition, single-stranded DNA may signal de novo methylation, so it may be possible that the formation of single strand breaks by oxidative stress may contribute to the modification of DNA methylation patterns observed in oxidant-transformed cell lines.
Cancer is a multistep process and often involves changes in the transcriptional activity of genes associated with many critical cellular processes for tumor development, such as proliferation, aging, inflammation, or metastasis. Both genotoxic and nongenotoxic mechanisms contribute to malignant transformation. Genotoxic mechanisms include changes in genomic DNA sequences that ultimately lead to mutations. Nongenotoxic include mechanisms (other than those directly affecting DNA) capable of modulating gene expression. ROS have been implicated at all stages of the cancerogenic process through the involvement of both types of mechanisms.
2.3 LncRNA in DNA methylation
Histone modification and chromosome remodeling, as well as transcription factors, play a key role in regulating DNA methylation across the genome in a site-specific manner. The human genome contains thousands of noncoding regions that for decades were considered “junk DNA” due to the lack of evidence for their transcription and lack of protein coding. In humans, less than 2% of the genome encodes proteins, but studies have shown that the genome, including noncoding regions, can be actively transcribed into noncoding RNAs (up to 75%). RNA transcripts >200 nucleotides that do not encode proteins are described as lncRNAs. According to version 42 of GENCODE, 19933 lncRNA genes and 57,936 lncRNA loci transcripts have been identified in the human genome. LncRNAs can not only affect gene expression itself but also regulate gene expression and various signaling pathways by, among other things, interacting with DNA methylation. LncRNAs can act both in the nucleus and in the cytoplasm. In the nucleus, lncRNAs regulate chromatin remodeling and transcription, and in the cytoplasm, lncRNAs regulate mRNA translation and turnover. They can interfere with signaling pathways, many of which will affect gene expression in a variety of biological and pathophysiological conditions. LncRNAs have been committed in the acquisition of all features of tumor cells, from intrinsic proliferation and survival capacity, to increased metabolism and association with the tumor microenvironment.
DNA methylation is variously mediated by lncRNAs, regulating the expression of target genes in many processes, including pathological ones. LncRNAs can recruit or repel DNA methyltransferases and TETs, control SAM/SAH levels to regulate DNMT activity, and regulate the expression of DNMTs and TETs [12]. LncRNAs play a versatile role in development and in various disease processes, including carcinogenesis. Through next-generation sequencing, thousands of lncRNAs have been identified as abnormally altered in cancer tissues. By regulating DNA methylation, lncRNAs can have a major impact on malignant transformation and tumor progression—proliferation, invasion metastasis, and in addition, abnormal DNA methylation regulates the expression of lncRNAs as tumor-suppressor genes [13]. Studies also show that the lung cancer-associated lncRNA LUCAT1 has been implicated in the development of many cancers, such as clear cell renal cell carcinoma, nonsmall cell lung cancer, glioma, osteosarcoma, colorectal cancer, and gastric cancer [13]. The same is true for the lncRNAs HOTAIR, PCAT1, MALAT1, and FAL1, which are involved in various human cancers [14]. However, most lncRNA genes, especially cancer-related lncRNAs, need to be annotated and further studied.
The mechanism of action of lncRNAs and the role of lncRNAs in DNA methylation may offer prospects for the development of novel cancer drugs, and furthermore, as shown by lncRNAs themselves, can be used to develop new agents for the early diagnosis of, for example, gastric cancer with a sensitivity close to 80% [13]. The US Food and Drug Administration have approved the testing of patient urine samples for lncRNA PCA3 to detect prostate cancer. Further lncRNA biomarkers have been identified in hepatocellular carcinoma—lncRNA HULC [15] and gastric cancer—lncRNA HULC and CCAT, which is also associated with colon cancer [16].
3. DNA methylation in selected cancer types and biomarkers
Whole-genome hypomethylation is one of the first abnormal methylation events to alter the methylation signature of cells in many cancers [17]. Hypermethylation of the APC gene promoter, a tumor-suppressor gene, can cause abnormal cell proliferation, cell migration, cell adhesion, cytoskeletal reorganization, and chromosome stability in various cancer types [18].
3.1 Biomarkers in gastric cancer and skin cancer
Similarly, in gastric cancer (GC), DNA hypermethylation of tumor-suppressor genes and DNA hypomethylation of oncogenes tend to induce multistep carcinogenesis [13]. For GC, more than 100 such genes have been found, and about 70 genes are significantly hypermethylated in tumor tissues compared to genes observed in normal tissues in GC patients. In GC, one of the most important suppressor genes is E-cadhedrin, hMLH1 or APC [19]. E-cadhedrin contributes to tumor progression by increasing proliferation, invasion, and metastasis [19]. Studies show that promoter methylation of genes such as RUNX3, RASSF1A, and Reprimo is much more frequent in GC tissues compared to normal tissues, indicating that promoter methylation of these genes may induce cancer tumorigenesis [20]. Gastric cancer is a very common malignancy, often diagnosed at an advanced stage and with a poor prognosis. GC formation and progression are associated with epigenetic modifications such as DNA methylation, chromatin remodeling, posttranslational modifications of histones or noncoding RNAs. MGMT promoter methylation is also associated with GC risk, but may not be a potential biomarker for GC [20]. The situation is different for melanoma (SC). For SC, hypermethylation of the MGMT promoter is associated with a significantly increased risk of disease, as is methylation of the RAR-β2 promoter [21]. However, as shown in a meta-analysis on SC, the best biomarker for early detection of SC is RASSF1A, whose methylation was significantly associated with melanoma risk, and its loss is associated with SC pathogenesis, and reduced RASSF1A expression is correlated with hypermethylation of the CpG island promoter region [21].
3.2 Biomarkers in colorectal cancer
Also in colorectal cancer (CRC), promoter hypermethylation by affecting key cellular pathways such as DNA repair, apoptosis, cell cycle regulation or angiogenesis is associated with silencing of tumor-suppressor genes [22, 23]. Abnormal DNA methylation also occurs during the transformation of chronic inflammation into CRC. Long-term intestinal inflammation leads to errors in immune surveillance mechanisms, contributing to the fact that anti-tumor immune responses are inhibited, which in turn leads to tumor progression [24]. Furthermore, DNA methylation is an endogenous mutation generator, increasing DNA damage and thus contributing to cell apoptosis. This fact shows that DNA hypermethylation is also related to age. There are also hypermethylated tumor-suppressor genes among age-dependent genes, such as estrogen receptor-1 (ESR1), SFRP1, or SYNE1 [25]. There are also other well-studied methylated genes in colorectal cancer, such as vimentin (VIM), cadherin-1 (CDH1), MLH1, TIMP metallopeptidase inhibitor-3 (TIMP3), secreted frizzled-related protein-1 (SFRP1), and hypermethylated in cancer-1 (HIC1) [24]. Studies show that there are two biomarkers already introduced for the noninvasive diagnosis of CRC, methylated syndecan-2 (mSDC2), and methylated SEPT9 (mSEPT9) [26, 27].
3.3 Biomarkers in endometrial cancer
Abnormal DNA methylation in certain tumor-suppressor genes and oncogenes is also responsible for the process of carcinogenesis in the endometrium. Endometrial cancer (EC) is a malignant tumor of the female genital tract that is one of the most common worldwide. The incidence of EC is steadily increasing and is higher in developed countries. Epigenetic mechanisms also play an important role in the development and progression of EC, and changes in DNA methylation are one of the most important epigenomic modifications that play a role in EC development [28]. Studies on EC have shown that promoter methylation of the suppressor gene RASSF1 is more frequent than in normal endometrium, and thus its expression is significantly reduced [29, 30]. Furthermore, RASSF1 methylation is also strongly correlated with EC risk and progression [31]. Multigene hypermethylation studies indicate that RASSF1 may be a potential biomarker in EC, as it is an important indicator of EC with high sensitivity and specificity [31]. It is rare in normal tissues, and RASSF1 promoter methylation is the most frequently inactivated gene identified among different cancer types.
3.4 Biomarkers in ovarian cancer, pancreatic cancer, and clear cell renal cell carcinoma
Studies of ovarian cancer (OC) and pancreatic cancer (PC) have shown that their progression is also linked to the accumulation of epigenetic changes. Women with advanced-stage OC have a five-year survival rate of less than 25%. Studies of DNA methylation markers have shown that, for OC cells, highly correlated with pathological fractions of OC cancer cells are, among others, the ZNF154 gene [32] and for PC, the SIM1, MIR129–2, and NR1I2 genes, which are specifically methylated in PC cells [33]. For OC, much attention has been paid to BRCA1 promoter methylation, as BRCA1 mutations are involved in hereditary OC. BRCA1 promoter hypermethylation occurs in 15–30% of cases of this cancer [34]. Nevertheless, studies indicate that ZNF154 methylation may serve better as a biomarker to detect OC and may also be a method capable of detecting multiple cancer types [35]. In the case of kidney cancer—clear cell renal cell carcinoma (ccRCC), such a biomarker appears to be hypermethylation of ZNF677 and PCDH8 [36].
DNA methylation profiling of tumor tissues is a valuable diagnostic tool for many types of cancer. DNA methylation data have become a valuable source of information for biomarker development. The discovery of functional and prognostic markers of DNA methylation in cancer provides both broader clinical opportunities and aids in the further development of epigenetic therapies. In addition, the DNA methylation data collected in The Cancer Genome Atlas (TCGA) helps to predict, for example, transcription factor (TF) regulators causing abnormal DNA methylation in different types of cancer, providing further therapeutic opportunities. Based on thousands of cancer samples of different types, TCGA collects, describes, and analyses data at clinical, molecular, and imaging levels, which are available in the Genomic Data Commons. The nature of DNA methylation aberrations in cancer and the stability of cell-free DNA in body fluids are of interest for the advancement of cancer diagnostics and therapy. The use of multiple target loci per test and genomewide epigenetic changes may help to improve the quality of tests under development (better sensitivity and specificity). Epigenetic modifications, related to tumorigenesis and cancer biology, as biomarkers specifically based on DNA methylation, due to the dynamic and reversible nature of this process, help to treat and improve therapies not only for cancer but also for other diseases (Table 1) [37].
Epigenetic biomarkers, in particular, not only DNA methylation but also histone modifications or miRNA regulation are induced by environmental factors, including through dietary habits and dietary components. Studies show that diet modulates DNA methylation [38] and has a significant contribution to the tumor-suppressive potential of tumors, at initiation, promotion, and progression stages [39]. Drugs usually act on single targets, whereas dietary components have multidirectional effects on tumors [39]. Studies have shown that some bioactive dietary components act as methyl donors or methylation cofactors or modifiers of DNMT enzymatic activity [8]. Diet and bioactive compounds in food (i.e. vitamins) have chemopreventive effects, able to act as epigenetic modifiers in tumor cells, disrupting the molecular mechanisms responsible for inappropriate DNA methylation patterns. Disregulation of epigenetic patterns, on the other hand, disrupts gene expression and can be the cause of tumorigenesis and other diseases [40]. To prevent and treat CRC, for example, the use of vitamins in combination with DNA methyltransferase inhibitors and other approved therapies seems promising [40, 41]. Nevertheless, studies show that dietary change and active lifestyle alone are already associated with altered DNA methylation patterns, in DNA regions with gene functions related to immune cell metabolism, tumor suppression, and general aging [38].
Nutri-epigenomics is a promising field that is rapidly developing, based on the growing knowledge of DNA methylation and its interactions dependent on bioactive nutrients and their action as epigenetic modifiers with implications for anti-cancer therapies.
Cancer epigenetics is pioneering potential applications of epigenetics in clinical treatment with epigenetics-based biomarkers successfully demonstrated in cancer diagnosis, prediction of tumor progression, and prediction of therapeutic response. Epigenetic biomarkers also have the potential to be used as screening tools. The role of DNA methylation and its abnormalities in cancer has been well documented in scientific studies.
Through DNA methylation profiling in tumor tissues, new entities have been identified or morphologically distinct cancers have been combined into appropriate entities, classifying cancers accordingly. Most importantly, however, DNA methylation patterns help to a great extent in the detection of even minimally invasive tumor tissue and are increasingly being used as a good diagnostic tool for many types of cancer. Unlike genetic alterations, DNA methylation is reversible, which makes it of great interest for therapeutic approaches. However, more information and research is still needed on the subject, and we may be able to prevent or cure cancer in the future.
Although great progress has been made in understanding the role of DNA methylation, and hypermethylated promoters serve as biomarkers, and only a few methylated genes or functional elements serve as clinically relevant cancer biomarkers. The bottleneck in the progress of DNA methylation has shifted from data generation to data analysis. Therefore, the next step is to develop machine-learning models for computational estimation of methylation profiling and identification of potential biomarkers and to create algorithms to predict DNA methylation modifications [42, 43]. A thorough understanding of DNA methylation mechanisms and prediction of DNA methylation modifications will be more effective to use for cancer diagnosis and therapy.
DNA methylation is a specifically regulated biochemical process, an epigenetic modification that plays a key role in human development and is important for the homeostatic control of the cell. During DNA methylation, epigenetic aberrations replace normal cellular signals that lead to tumor initiation and propagation. DNA methylation profiling follows the continuous technological improvements of DNA methylation assays, which in turn can provide an enormous amount of data. It is also an important aspect of understanding malignant transformation and is becoming an increasingly important tool for diagnosing cancer (increasing the accuracy of diagnosis), predicting prognosis, and monitoring therapy. With an increasingly accurate and comprehensive understanding of the mechanism based on DNA methylation, better and better drugs can be created that target the epigenetic machinery of the cell as anti-cancer therapies. However, despite significant advances in the knowledge of DNA methylation in translational research, many challenges remain. Having understood the role of DNA methylation, the next challenge facing the community is to decipher the role that DNA methylation derivatives play in cancer. We have also only just begun to fully understand the genomewide demethylation process and the impact that methylation intermediates have on tumor development, diagnosis, and treatment. Expanding our knowledge of cancer treatment strategies will be greatly influenced by the growing field of epitranscriptomics, or understanding aberrations in DNA methylation of retroviruses. Thanks to projects such as TCGA or the Cancer Cell Line Encyclopedia, which provide genomic, epigenomic and transcriptomic data, early cancer detection therapy combined with personalized treatment is no longer just a dream.
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Written By
Ewelina A. Klupczyńska
Submitted: 15 November 2022Reviewed: 13 February 2023Published: 08 March 2023
Open access peer-reviewed chapter
