Open access peer-reviewed chapter - ONLINE FIRST

Epigenetic Regulation in Cancer and Cancer Therapies

Written By

Mehak Sharan, Runjhun Mathur, Niraj Kumar Jha, Khushboo Rana, Saurabh Kumar Jha and Abhimanyu Kumar Jha

Submitted: January 8th, 2022 Reviewed: February 16th, 2022 Published: May 5th, 2022

DOI: 10.5772/intechopen.103768

IntechOpen
Squamous Cell Carcinoma Edited by Sivapatham Sundaresan

From the Edited Volume

Squamous Cell Carcinoma [Working Title]

Dr. Sivapatham Sundaresan

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Abstract

It has been believed that identification of alterations in epigenetic profiles can be used to distinguish not only between various types of malignancies but also between different phases of cancer progression. As a result, epigenetic factors have a lot of potential to become more accurate diagnostic and prognostic biomarkers for many malignancies. Although DNA methylation is the most researched aspect of epigenetics, only a few methylation markers are routinely used in clinical practice. DNA methylation biomarkers, on the other hand, are expected to play a significant role in the near future. To summarize, epigenetic regulation plays a critical role in cancer development, and epigenetic biomarker analysis has a lot of potential to become clinically useful. More research is needed to further develop and evaluate epigenetic biomarkers\' therapeutic use.

Keywords

  • epigenetics
  • biomarkers
  • cancer
  • tumour suppressor genes
  • oncogenes
  • hypermethylation

1. Introduction

Cancer is a disease where some body’s cells grow uncontrollably and spread to other parts of the body. The human cells can grow fast and multiply by cell division to forming new cells as the body required. When cells are growing old, damaged, or die, then new cells take their place. Sometimes the process of cycle breaks down, and abnormal or damaged cells can grow and multiply. This abnormal growth of cells may form tumours, which are lumps of tissue. Tumours can be divided into two types; cancerous or not cancerous (benign). Cancerous tumours spread into, or invade, nearby tissues which can travel to different places in the body to form new tumours by a process called metastasis. Cancerous tumours are called as malignant tumours. Sometimes benign tumours can also cause various serious symptoms in life; to be life-threatening, such as benign tumours in the brain. Cancer has long existed for all of human history [1]. In the earliest written history record, cancer has been circa 1600 BC in the Egyptian Edwin Smith Papyrus which is described as breast cancer [2].

In the fifteenth to seventeenth centuries, it became accepted by doctors to dissect bodies and discover the reason to cause of death [3]. According to German professor Wilhelm Fabry, it was believed that breast cancer was caused due to a milk clot in a mammary duct. His contemporary Nicolaes Tulp believed that it was a poison that can spreads slowly through outcome chemical process and acidic lymph fluid [4].

Cancer is a kind of disease which involves abnormal cell growth with lot of potential to invade or spread to other parts of the body [5, 6]. These contrast with benign tumours, which do not spread [7]. These symptoms including a lump, abnormal bleeding, prolonged cough, unexplained weight loss and a change in bowel movements [8].

Tobacco is one of the leading causes of cancer death, accounting for around 22% of all cancer fatalities [9]. Obesity, poor diet, lack of physical activity and excessive alcohol consumption account for another 10% of deaths [6, 7, 8]. Other concerns include diseases, ionizing radiation exposure and exposure to contaminants in the environment [10]. Helicobacter pylori, hepatitis B, hepatitis C, human papillomavirus infection, Epstein-Barr virus and human immunodeficiency virus (HIV) cause 15% of malignancies in the poor world [11]. Inherited genetic abnormalities are responsible for 5–10% of cancer cases [12].

No smoking, maintaining a healthy weight, limiting alcohol intake, eating plenty of vegetables, fruits and whole grains, vaccination against certain infectious diseases, limiting consumption of processed meat and red meat and limiting exposure to direct sunlight are all factors that can help prevent cancer [13, 14]. Cervical and colorectal cancers can be detected early by screening [15]. The benefits of breast cancer screening are debatable [15]. Radiation therapy, surgery, chemotherapy and targeted therapy are frequently used to treat cancer [5, 8]. In 15-year-old children who have been diagnosed with cancer, the 5-year survival rate for cancer in the industrialized world is on average 80%. The average 5-year survival rate in the United States is 66% [16].

About 8.8 million deaths were caused in 2019 (15.7% of deaths) [17]. The most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer and stomach cancer [18]. In females, the most common types are breast cancer, colorectal cancer, lung cancer and cervical cancer [19].

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2. Causes of cancer

Genetic alterations generated by environmental and lifestyle factors cause 90–95% of cancer cases [8]. Inherited genetics is responsible for the remaining 5–10% [8]. Environmental influences include, lifestyle, economic and behavioural factors, as well as pollution, but they are not inherited. Tobacco use (25–30%), food and obesity (30–35%), infections (15–20%), radiation (both ionizing and non-ionizing, up to 10%), lack of physical activity and pollution are all common environmental factors that can contribute to cancer death [8, 19]. Psychological stress does not appear to be a risk factor for cancer start [19, 20], but it may affect outcomes in people who have already been diagnosed with cancer [20].

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3. Epidemiology

The cancer epidemiology provides the various types of essential information on causes and population trends of these conditions. It is possible to establish timely and appropriate healthcare interventions aimed at developing efficient policies for prevention, screening and diagnosis [1]. Recently, a concise overview on current cancer epidemiologic data is described which was gathered from the official databases of the World Health Organization (WHO) and American Cancer Society (ACS) in an attempt of providing updated information on frequency, mortality and survival expectancy of the 15 leading types of cancers worldwide. According to estimates, there were 18.1 million new cancer diagnoses and 9.6 million deaths worldwide in 2018 [20] as shown in Figure 1. About 20% of males and 17% of females will develop cancer at some point in their lives, with 13% of males and 9% of females dying from it [20].

Figure 1.

Estimates of deaths due to cancer in 2018.

In 2008, around 12.7 million malignancies (excluding non-melanoma skin cancers) were diagnosed, and nearly 7.98 million people died [18]. Cancer is responsible for about 16% of all fatalities. Lung cancer (1.76 million deaths in 2018), colorectal cancer (860,000), stomach cancer (780,000), liver cancer (780,000) and breast cancer (620,000) are the most common [5]. Invasive cancer is thus the major cause of death in developed countries and the second leading cause in developing countries [19]. The developing world accounts for more than half of all cases [20].

In 1990, 5.8 million people died of cancer [18]. Longer life spans and lifestyle changes in the developing countries have contributed to an increase in deaths [18]. Age is the single most important risk factor for cancer [19]. Although cancer can strike at any age, the majority of people with aggressive cancer are over 65 [20].

Aging's effect on cancer is complicated by factors such as DNA damage and inflammation promoting it and factors such as vascular aging and endocrine changes inhibiting it [20].

Leukaemia (34%), brain tumours (23%) and lymphomas (12%) are the three most prevalent childhood cancers [20]. In the United States, one out of every 285 children is diagnosed with cancer. Childhood cancer rates grew by 0.6% per year in the United States between 1975 and 2002 and by 1.1% per year in Europe between 1978 and 1997 [20].

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4. Types of cancer

A total of 100 cancer kinds have been found. Cancers are frequently called after the organs or tissues in which they develop. Lung cancer, for example, begins in the lungs, while brain cancer begins in the brain. Cancers can also be classified based on the type of cell that caused them, such as epithelial or squamous cells. Most cancers are named for the organ or type of cell in which they start—for example, cancer that begins in the colon is called colon cancer; cancer that begins in melanocytes of the skin is called melanoma. The following includes a description of the major cancer types.

4.1 Brain and central nervous system cancer

Cancers of the brain and central nervous system (CNS) are abnormal cell growths in the brain and spinal cord tissues. Primary brain tumours are cancers that start in the brain. A metastatic brain tumour is a tumour that begins in another part of the body and travels to the brain.

It may be either benign (not cancer) or malignant (cancer). The symptoms of brain and spinal cord tumours depend on where the tumour forms, its size, how fast it is growing and the age of the patient. In adults, anaplastic astrocytomas and glioblastomas make up about one-third of brain tumours. In children, astrocytomas are the most common type of brain tumour. Seizures, drowsiness, confusion and behavioural abnormalities are only some of the signs of brain cancer. Although the causes of brain tumours are unknown, several risk factors include hereditary or genetic disorders, as well as exposure to extremely high doses of radiation to the head. Surgery, radiation, chemotherapy or steroid therapy, or a combination of these treatments, may be used to treat brain tumours [20, 21].

4.2 Breast cancer

Breast cancer is a disease in which the cells of the breast grow out of control. It only affects women. Ductal carcinoma is the most prevalent type of breast cancer, which begins in the cells of the ducts. Breast cancer develops in the cells of the lobules and other breast tissues. Breast cancer spreads to surrounding tissue from where it begins in the ducts or lobules. Many forms of breast cancer can develop a lump in the breast, but not all of them do. New lumps or thickening in the breast or under the arm, nipple discharge or turning in, nipple ulcers, skin of the breast dimpling and rash or red swollen breasts are some of the signs and symptoms. The causes of breast cancer are unknown, but risk factors include increasing age, family history, inheritance of mutations, exposure to female hormones (natural and administered), obesity (poor diet and inadequate exercise) and excess alcohol consumption [22, 23].

4.3 Cervical cancer

Cervical cancer happens when abnormal cells on the cervix, the lower part of the uterus (womb), grow out of control. Squamous cell carcinoma (which accounts for 80% of cases) and adenocarcinoma are two types of cervical cancer. The thin, flat cells that border the cervix are where squamous cell cancer develops. Cervical cells that produce mucus and other fluids are where adenocarcinoma originates. Because it begins higher in the cervix, adenocarcinoma is less prevalent and more difficult to identify. Cervical cell alterations that occur early on rarely cause symptoms. Vaginal bleeding in between periods, menstrual bleeding that is longer or heavier than usual, bleeding after intercourse, pain during intercourse, unusual vaginal discharge, vaginal bleeding after menopause, excessive tiredness, leg pain or swelling and low back pain are some of the most common symptoms. Almost all occurrences of cervical cancer are caused by long-term infections with certain forms of human papillomavirus. The other major cause of cervical cancer is smoking. Cervical cancer can be squamous cell carcinoma (accounting for 80% of cases) and adenocarcinoma. Squamous cell carcinoma begins in the thin, flat cells that line the cervix. Adenocarcinoma begins in cervical cells that make mucus and other fluids. Adenocarcinoma is less common and more difficult to diagnose because it starts higher in the cervix. Early changes in cervical cells rarely cause symptoms. The most common signs are vaginal bleeding between periods, menstrual bleeding may be longer or heavier than usual, bleeding after intercourse, pain during intercourse, unusual vaginal discharge, vaginal bleeding after menopause, excessive tiredness, leg pain or swelling and low back pain. Long-lasting infections with certain types of human papillomavirus cause almost all cases of cervical cancer. The other main risk factor for cervical cancer is smoking. Treatment may include surgery, radiation therapy, chemotherapy or a combination. The choice of treatment depends on the size of the tumour and disease stage [24, 25].

4.4 Oesophageal cancer

Oesophageal cancer forms in the tissues of the oesophagus. The most common types of oesophageal cancer are squamous cell carcinoma and adenocarcinoma. The upper and middle oesophagus are the most common sites for this malignancy; however, it can arise anywhere throughout the oesophagus. Epidermoid carcinoma is another name for this condition. Adenocarcinoma is a cancer that starts in glandular (secretory) cells, which produce and leak mucus and other fluids. It normally develops near the stomach in the lower section of the oesophagus. Oesophageal cancer is increased by smoking, heavy alcohol consumption and Barrett oesophagus. Barrett oesophagus and gastroesophageal reflux disease may raise the risk of oesophageal cancer. Weight loss, hoarseness and cough and painful or difficult swallowing are all signs and symptoms of oesophageal cancer. Because there are no early indications or symptoms, oesophageal cancer is frequently identified at an advanced stage. Doctors frequently prescribe combining multiple types of treatment for persons with tumours that have not migrated beyond the oesophagus and lymph nodes, such as radiation therapy, chemotherapy and surgery. The order in which therapies are given varies depending on a number of criteria, including the type of oesophageal cancer [26, 27].

4.5 Head and neck cancer

About 90% cases of cancers found in head and neck begin in the squamous cells that line the moist, mucosal surfaces inside the head and neck and are known as head and neck squamous cell carcinoma (HNSCC). HNSCC is the sixth leading cancer by incidence worldwide. The tumour, node, metastasis (TNM) staging system may be often used to classify patients with HNSCC and also based on the clinical, radiological and pathological examination of tumour specimens [28]. Head and neck cancer area may become metastatic and spread to several types of organs or tissues such as the brain and lung through lymphatic and blood vessels. Amplification of region 11q13, 7p11 and other chromosomal aberrations have also been linked to HNSCC progression [29]. Tobacco usage and alcohol use are two of the most dangerous risk factors associated to this malignancy: a lump or sore that does not heal, a persistent sore throat, difficulty swallowing, a change or hoarseness in the voice and other symptoms [30]. Patients with HNSCC have a 5-year survival rate of approximately 40%–50%. If discovered and treated early, head and neck cancer is highly curable [31]. Chromosomal abnormalities such as amplification of region 11q13, 7p11, etc. are also associated with HNSCC aggravation [29]. There are several risk factors linked to this cancer, the most vicious ones are tobacco use and alcohol consumption. Symptoms may include a lump or sore that does not heal, a sore throat that does not go away, trouble in swallowing, a change or hoarseness in the voice, etc. [30]. The 5-year survival rate of patients with HNSCC is about 40%–50%. Head and neck cancer is highly curable if detected and treated early [31]. Head and neck cancer can be managed either in prophylactic manner, i.e. stoppage of alcohol consumption and smoking habit, grinding of sharp cuspal teeth, ultrasonic scaling, etc. or through definitive management such as surgical removal, chemotherapy, etc.

4.6 Liver cancer

Liver cancer is called as hepatic cancer or hepatocellular carcinoma. It starts from the tissue of the liver. In other words, it is a primary liver cancer. Cancer is spread from elsewhere to the liver, known as liver metastasis which is more common than primary liver cancer. Liver cancer is rare in children and teenagers, but there are two types of liver cancer that can form in children Cholangiocarcinoma is another name for bile duct cancer. Intrahepatic cholangiocarcinoma is a type of cancer that begins in the bile ducts of the liver. Extrahepatic cholangiocarcinoma is a type of cholangiocarcinoma that begins in the bile ducts outside of the liver. Compared with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma is substantially more prevalent.

The signs and symptoms of liver cancer are often not felt or detected until the illness has progressed significantly. Unintentional weight loss, loss of appetite, feeling very full after eating, even if the meal was modest, feeling ill and vomiting, pain or swelling in your abdomen (tummy), jaundice and itchy skin are some of the symptoms that might occur [32, 33, 34].

4.7 Leukaemia

Leukaemia is a hematopoietic stem cell–initiated heterogeneous disease which occurs in abnormal blood cell proliferation in the bone marrow and peripheral blood [35]. It can affect very fast (lymphocytes or myelocytes). The four main types of leukaemia may include chronic lymphocytic leukaemia (CLL), acute lymphocytic leukaemia, acute myelocytic leukaemia and chronic myelocytic leukaemia. Leukaemia is usually present in white blood cells. However, red blood cells and platelets may also become cancerous. Pain in the bones or joints, swollen lymph nodes that do not really hurt, fever or night sweats, feeling weak or weary, bleeding and bruising easily, frequent infections, discomfort or swelling in the belly, weight loss or loss of appetite are all common symptoms of chronic or acute leukaemia. Chemotherapy is used to treat the majority of leukaemia patients. Radiation therapy /or bone marrow transplantation may be used in some patients [36, 37].

4.8 Lung cancer

Lung cancer is a form of cancer that starts in the trachea (windpipe), bronchus (main airway) or lung tissue. Non-small-cell lung cancer and small-cell lung cancer are the two most common kinds of lung cancer. Squamous cell carcinoma, adenocarcinoma and large cell carcinoma are all subtypes of non-small-cell lung cancer. Small cell lung cancer is also called oat cell cancer. About 10%–15% of lung cancers are small-cell lung cancers. Cigarette smoking is the principal risk factor for development of lung cancer, but many people with the condition eventually develop symptoms including a persistent cough, coughing up blood, persistent breathlessness, unexplained tiredness and weight loss and an ache or pain when breathing or coughing. Treatment of lung cancer can involve a combination of surgery, chemotherapy and radiation therapy as well as newer experimental methods

4.9 Pancreatic cancer

Pancreatic cancer is caused due to abnormal and uncontrolled growth of cells in the pancreas—a large gland that is part of the digestive system. Adenocarcinomas are most commonly found in gland cells in the pancreatic ducts, although they can also occur in pancreatic enzyme cells (acinar cell carcinoma). Adenosquamous carcinomas, squamous cell carcinomas and giant cell carcinomas, all named by their appearances under a microscope, are further types of pancreatic tumours linked to exocrine activities. For example, insulinomas (insulin), glucagonomas (glucagon), gastrinomas (gastrin), somatostatinomas (somatostatin) and VIPomas (vasoactive intestinal peptide or VIP). Functioning islet cell tumours still make hormones, while nonfunctioning ones do not. Symptoms may include abdominal pain, weight loss, diarrhoea and jaundice. They can also be caused by conditions such as pancreatitis (inflammation of the pancreas), gallstones, irritable bowel syndrome or hepatitis (inflammation of the liver). Smoking is one of the most important risk factors for pancreatic cancer. Heavy exposure at work to certain chemicals used in the dry cleaning and metal working industries may raise a person’s risk of pancreatic cancer. Surgery, radiation and chemotherapy are the most common treatment types.

4.10 Prostate cancer

Men are the only ones who get prostate cancer. The prostate gland, which is part of the male reproductive system, is where cancer starts to grow. Localized prostate cancer, also known as early prostate cancer, is cancer that is contained within the prostate and does not cause any symptoms. Adenocarcinomas are the most common type of prostate cancer (cancers that begin in cells that make and release mucus and other fluids). Early indications of prostate cancer are frequently absent. Men with advanced prostate cancer may have more frequent urination or a weaker urine flow, although these symptoms can also be caused by benign prostate diseases. The following symptoms may occur if a tumour causes the prostate gland to enlarge or if cancer spreads beyond the prostate: Frequent urination, a painful or burning sensation during urination or ejaculation, blood in urine or sperm and pain or stiffness in the lower back, hips, pelvis or thighs are all symptoms of urinary incontinence. In fact, males over the age of 65 account for more than 65% of all prostate cancer diagnoses.

Various other cancers are bladder cancer, colorectal cancer, gastric cancer, sarcoma, kidney cancer, lymphoma, melanoma, ovarian cancer (Table 1).

Table 1.

Types of cancer and body parts it affects.

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5. Epigenetic factors

The abnormal patterns such as the change in composition of chromatin or organization of chromatin, DNA methylation, disrupted patterns in the post translational modifications of histone are known as the epigenetic alterations. These changes in the epigenomes might occur by the disruption on the epigenetic machinery which are associated with the mutated patterns of the wild-type genes expressions along with their changed states. In the process of tumorigenesis, the epigenetic component recognition is important for a better understanding of the cancer along with new research in treatment, detection and prevention of cancer. The mutations in oncogene or the signalling gene in any human cancer are dominant that lead to formation of tumours and cancer. For an instance, the activity of the product of gene for growth stimulation is enhanced due to the mutation in the gene, ras. These types of epigenetic silencing of tumour suppressor genes or the genetic mutations in these genes are often observed to be recessive that requires the disruption in both the copies of alleles in order to get the full expression of the phenotype which is transformed.

Two or multiple-hit hypothesis:According to the study of Knudson [38] in 2001, the hypothesis of the two or multiple hit was proposed as the idea that in the malignant cell line, the two copies of tumour suppressor genes have to be incapacitated. The three classes’ hits can work in combinations of different types in order to cause the complete loss of activity of tumour suppressor genes. The mutations in the coding sequence along with loss of either entire copies or part of copies of genes, the silencing of epigenetics might occur to cooperate to lead to disable the control of gene.

There are studies that signify that the cancers harbour the mutations that are frequent in genes for the epigenetic machinery that lead to abnormalities in epigenome. These abnormalities affect the gene patterns of expressions along with the stability [39]. There are genes that are frequently mutated, especially the ones that encode proteins responsible for the normal chromatin control of the DNA methylation [40]. These patterns are important to understand the cancer biology along with the new discoveries in the cancer therapy. The epigenetic activation or silencing of genes may lead to cells for mutations such as the epigenetic silencing of the MLH1 DNA repair protein as it leads to lack of efficient DNA repair. There are epigenetics processed that regulate the genome and could be downregulated in cancer.

Whole exon sequencing, genome-wide DNA methylation, RNA expression, whole genome sequencing and chromatin analyses’ results showed the understanding of the epigenomes in the normal and cancer cells [41]. This signified that the epigenetic control not only comprises the coding genes but also the microRNAs, non-coding RNAs and other genome regulatory functions [42]. These mutations are present in high frequencies and known as the ‘driver’ mutations that result in the disruption of the epigenome by mutations for the invasion and progression of cancer. These epigenetic changes take place independently of the mutations in factors of chromatin modification where the damage and heritable alterations are induced due to the physiological or environmental events in cancer progression or inheritance of cancer risk states [43].

The very first proposal of the alteration in DNA methylation as a contribution to cancer was the discovery of the methylation of the cytosine in DNA to become 5-methylcytosine. There have been many studies on 5mC alterations and its distribution pattern that can help to distinguish it from the normal cells with the result of three major routes. The three major routes involved in the CpG methylation in the oncogenic phenotype are by: hypomethylation on oncogenes, hypermethylation of tumour suppressor genes and mutagenesis of 5mC by UV radiation, carcinogens or deamination [44].

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6. Hypomethylation of oncogenes

The DNA methylation changes in cancer cells with regional modifications which is recognized as the global DNA hypomethylation by the genome-wide analyses [45]. The genomic instability with increase in aneuploidy is the result of the DNA demethylation that could act as a hallmark of cancer. The reduction and deletion of DNA methyltransferase, DNMT1 could result in the tumour induction along with increased mutation and aneuploidies rates. It clearly indicates the chromosomal fragility [46]. The activation of transcription by transcription of oncogenes, repeats and transposable elements is accompanied by the loss of DNA methylation [45]. The activation of the transposable elements acts as source of potential mutations during the process of transposition. The genome has CpG islands which are around 80% methylated, and in cancer this methylation rate drops to 40–60%. The mapping technologies available could be useful in detecting the patterns more precisely. About one-third of the genome could be covered with the blocks of DNA hypomethylated blocks of 28kb–10Mb. The cause of this is hypothesized by many theories such as the DNA hypomethylation could be associated with broad shifts in chromatin organization that could result in mutations affecting the homeostasis of DNA methylation.

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7. Direct mutagenesis

The methylation of the cytosine in somatic cells is more than one-third of all the transitional mutations observed. The somatic mutations in the cancer-causing p53 gene were studied (Rideout et al. 1990). This mechanism is common in somatic tissues and forms many inactivating mutations in tumour suppressor genes due to the methylation of the fifth position of cytosine ring that in the double-standard DNA increases the hydrolytic deamination. The product of deamination of 5mC is thymine and not uracil, and so the DNA repair mechanism is less efficient to repair this mismatch. For example, among all the p53 mutations, more than 50% of the mutations or methylation occurs in the cytosine area [47]. Thus, the risk of the cancer increases by the endogenous mechanism. The cytosine methylation favours the carcinogenic adducts between the carcinogens and DNA like the cigarette smoke that result in the increased mutation sites in the CpG sites of lungs [47]. This type of direct mutagenesis and DNA methylation can also alter the rate of mutations by factors such as sunlight-exposed skin as the methyl group changes the absorption spectrum for cytosine into normal incident sunlight [47].

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8. Hypermethylation of TSG

The abnormal hypermethylation of the CpG islands in the five regions of cancer-related genes is associated with the transcriptional silencing along with the alternative mechanism to inactivate the tumour suppressor genes by mutation [48]. In normal development or the cell renewal systems, around 60% of all the gene promoters have then non-methylated CpG islands. This non-methylation of the chromatin is either active or ready to be activated to express the genes. The prevalence of the methylated CpG island promoters in the cancer cells is more that leads to conclusion that they are directly involved in the carcinogenesis. This could lead to new era of cancer therapy by the reversal of the epigenetic changes observed in cancer [49]. The methylation of the gene body gives rise to elongation during transcription and enhancing the gene expression; thus, 5mC is more common in gene body of active genes and is associated with this rather than repression [50].

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9. Aberrant hypermethylation

The loss of function of gene acts as a mediator between the abnormalities caused by epigenetic and genetic changes. There is always a debate over the cause of cancer to be genetic or epigenetic. Although the combination of these two factors works towards the tumour progression. The chromatin changes that lead to the gene function changes are important to understand the cancer mechanism and to develop the early detection and profiling of tumour with new targets for its prevention.

The silencing of genes that are important for transcription as they are associated with methylation of DNA in promoter regions of unmethylated gene [51, 52]. The increased emphasis on the delineation of the genes with new screening approaches now holds the important feature in research [53, 54]. In human cancers, there are number of genes that are hypermethylated which are mutated in the germline [1]. The common examples of hypermethylated genes are BRCA-1, MLH1, VHL, APC, E-cadherin, Rb, LKB1 and p16. They exhibit the non-familial cancers changes along with selective advantage in several ways for the loss of function of gene [55].

There are three types of characteristics of the aberrant hypermethylation: There are genes where the hypermethylation is observed in the specific tumour types. Secondly, there are genes that predict the phenotype of the tumour by the loss of specific function by epigenetic and genetic changes. Thirdly, there could be disruption in the pathways of the cells. There are several hyperemethylated genes, and in some of the genes, the methylation of the promoter is the only type of inactivation detected in the cancer as other genes are either rare or not have been observed. Each of the genes that are detected as hypermethylated must be identified and studied for its role in tumour type and progression. This is crucial as according to some studies, the genes that are hypermethylated could be mutated in a group and be responsible for the change in process or processes in biology of cancer such as in the repair of mismatch mutation [56, 57]. The non-critical and critical loci are affected by both the processes, leading to tumour development by loss of function of the key gene.

The CpG islands that are hypermethylated have been identified as a guide to clone the tumour suppressor genes that are frequently observed to be deleted in several cancers, but no genetic alterations have been identified in the tumour suppressor genes [58]. For example, the member of the zinc-finger transcription factor family, HIC-1, showed its importance in the process of development in hypermethylation in many tumours [59, 60] and also upregulated by the protein, p53 [10, 13]. The role of the gene is still under study, but the death of mice during embryogenesis from various defects has been observed during the knock-out of HIC-1 [61]. This information obtained is very helpful because of the databases built up for the chromosome positions where the gene is located and helps in screening of the hypermethylated loci in the DNA of the tumour cells.

Hypermethylation is the early event in the progression of tumour, and when the hypermethylated promoter region increases in the normal cells and tissues, that mark the early stage. In tumorigenesis, the promoter hypermethylation of genes plays a vital role that could be detected in the early stages. The early losses of the control of the cell cycle, disruption of cell-to-cell signalling, altered transcription factors and genetic instability are the early genetic alterations to characterize human cancer. Loss of function of p16 gene by the epigenetic loss helps to pass the check points of the mortality to enter in onset of cellular immortality in carcinogenesis [62, 63] along with tumours in early stage [64, 65]. In colon cancer, the gatekeeper gene, APC, which is responsible for the transcription pathway of beta-catenin-TCF transcriptional pathway, gets hypermethylated, leading to onset of colon cancer [66]. Similarly, in breast cancer, the hypermethylation of E-cadherin promoter disrupts the cell-to-cell recognition that is observed in the early stages [67].

There are some basic differences between the promoter hypermethylation caused by genetic and epigenetic factors. Firstly, the loss of gene function with promoter hypermethylation is relatively more subtle selective than mutation in the tumour progression. As in genetic events, both alleles are disrupted in two-hit paradigm for loss of gene function of tumour suppressor gene. In this, the first genetic hits result in the haplo insufficiency states [68]. On the contrary, the loss of the gene transcription is related to aberrant hypermethylation of CpG island, which is mediated by the region-oriented methylation density [69]. This density can increase over time by the cell replication which is associated with the increase in transcription loss [70]. Secondly, the aberrant hypermethylation and gene silencing are potentially reversible even after being very stable in cancer cells, but the mutations on genetic level are not [71]. Most of the cells in epithelial tumours can form metastatic foci and could be highly invasive and can help in the invasion of tumour cells. This invasion requires re-expression of E-cadherin so that cell aggregates are formed by tumour cells to survive in the foreign environment [72]. This heterogeneous loss of E-cadherin in tumour sites of both primary and metastic phases in same patient is similar [73, 74]. Loss of function of E-cadherin is very common in epithelial cancers and mainly related to the promoter hypermethylation as the heaviest promoter hypermethylation occurs in most highly invasice cells [37]. Thus, the reversibility of the aberrant hypermethylation plays a key role in the dynamic of the cell population to detect the behaviour of tumour. The chromatin formation dynamics in the DNA methylation along with the deacetylation of histone works in tumours to silence the hypermethylated genes. There are certain hypermethylated genes that do no re-express even by the agents such as Trichostatin. This drug is although effective for minimal de-methylation. 5-aza-cytidine is the demethylating drug that could be used to achieve demthylation even in the low doses [75].

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10. Tumour suppressor genes

During interaction between cells with its surroundings and cell proliferation, there are specific controls at every step, but alterations in them lead to tumour formation and its metastasis. This causes disturbance in the relation between the number of cells increment during cell division or decrease in number of cells due to apoptosis or differentiation. There are positive and negative signals that control the cell multiplication and the homeostasis maintenance, their effects are based on the genetic changes that affect the control points due to the tumorigenicity [76]. The malignancy is due to the genetic changes and control points which is now possible to identify and characterize. There are several changes detected in genes that led to tumour formation, and these alterations may have positive influence or can involve in inhibition of cell growth [77]. Tumorigenesis is a multi-step process that requires the different genetic changes with proper mechanism to be interpreted from the epidemiological studies. The altered cells population may increase due to the expansion of genetic change that leads to larger target pool of subsequent genetic changes. These alterations are mainly deletions and point mutations that lead to loss of function of genes that interfere with the process of restraining cell multiplication, leading to oncogenesis. This genetic alteration could give positive signals such as gene overexpression that could lead to gene amplification in signal transduction element that acts as a stimulus to cell proliferation.

There are different terms that are being used for these altered genes such as anti-oncogenes, tumour suppressor genes or recessive oncogenes. The terminology of these genes still does not satisfy the mechanism of their work as their existence to only inhibit action of oncogenes is not confirmed. Although there are genes that inhibit the proliferation and expression of proto-oncogenes. The negative influence of these genes has been confirmed by the neoplastic transformation, loss of heterozygosity in tumours and familial cancer. Loss of function of the normal alleles leading to the neoplastic transformation is the primary evidence by somatic cell hybrid experiment of genetic alterations. When injected into the host without loss of chromosome, none of the hybrids that were generated between tumorigenic and non-tumorigenic cells gave rise to tumours [78]. Thus, the rise of tumours from tumorigenic hybrid cells was confirmed by the specific chromosome losses which is usually suppressed in the normal cells. This phenomenon was achieved by the wide variety of tumour suppressor genes that were suppressed by the mutations or genetic alterations which lead to recessive genetic changes, complemented by the normal alleles from normal parents. There have been cases where the combinations of the tumour cell lines and non-tumorigenic cell line both showed the recessive changes that signified the presence of multiple alterations or combination of it [79]. There are several tumour suppressor genes reported for different cancers.

11. P53

TP53 is the gene that is responsible for the protein p53. This a gene is known as the guardian of the genome or the caretaker gene. This protein serves different functions in the cell such as regulation of cell cycle, DNA repair, transcription and apoptosis induction. When this tumour suppressor gene gets mutated, that leads to cause many cancers. It comprises 37% of the cancers reported in the world with 6.5 million diagnosed cases. The homozygous loss of this gene leads cancers with percentage of 65% in colon cancers, 50% in lung cancer and 30–50% in the breast cancers [80]. In leukaemia, sarcomas, lymphomas and neurogenic tumours, loss of p53 is also reported.

12. pRB

The first tumour suppressor protein that was discovered was pRB in the human retinoblastoma. It is a tumour survival factor that acts as a gatekeeper gene that functions in the cell division and death regulation and cell proliferation [81]. If mutation occurs in this gene, then the function is lost, and there is no control in the cell division leading to unlimited growth.

13. BCL2

The family of proteins either inhibits or induces cell apoptosis along with maintaining the mitochondria composition. The signalling cascade from mitochondria till the cell apoptosis is performed due to this gene [82].

These are the epigenetic factors that are involved in the regulation of cancer. There are many studies conducted to discover the epigenetic regulation in many cancers. One of the cancers with 54.5% mortality rate (WHO, 2018) is cervical cancer. There are many epigenetic regulations studied under it.

14. Epigenetic regulation in cervical cancer

DNA methylation and histone acetylation are the two most widely studied epigenetic factors. Although there are certain different factors such as RNA interference that could be responsible for the transcriptional silencing [83]. The main epigenetic alterations involved in the cervical cancer are illustrated in Figure 2.

Figure 2.

Epigenetic alterations involved in the cervical cancer.

Hypermethylated and hypomethylated genes:In the development of cervical cancer, infection by high risk type Human Papillomavirus (HPV) is one of the main causes. HPV 16 and HPV 18 are the two most known viruses to cause cervical cancer. In the genome of HPV, there are certain epigenetic changes that could be responsible for the carcinogenic process driven by the virus along with the genome of the host. The methylation machinery activation is one of the defence mechanisms adopted by the host during infection, when the viral gene is inserted into the host genome [84]. The activation of the silenced sequences in the human genomic DNA sequence with long terminal repeats and transposable elements could play a role in the process of cancer [85]. Viruses have the ability to regulate the expression of genes by methylation them in order to silence their activity to favour the infection [85]. On the other hand, viral genome can also synthesize oncoproteins that could either indirectly or directly silence the genes that may act against the tumour promotion. In a study of transfection of cell having methylated genome with HPV-16, it was observed that the DNA was transcriptionally repressed [86]. SiHa and CasKi are the two forms of cervical cancer cell lines that harbour the HPV-16 infection and have multiple viral genome copies. In one of the cases, it was found by the help of McfBC enzyme that the both cell lines when infected with HPV-16 have a conserved CpG hypo and hypermethylated genes. Hypermethylation of genes was found in 52% of the smears from asymptomatic women, 21.7% in pre-invasive lesions and 6.1% invasive case smears. Hypomethylation of LCR and E6 gene region of the oncogene was also observed. On the contrary to the first case study, high methylation frequency at most sites in carcinomas was found as compared with dysplasia and chromosomal integration in invasive lesions [87]. HPV 18 study was also studied in the two cervical cell lines, HeLa and C4-1. A clonal heterogeneity in the status of methylation was reported along with promoter methylation in 50% cancers and 66% smears. This resulted in the conclusion that the viral oncogenes in lesions are the result of their activity level in transcription and not neoplastic progression.

In HPV life cycle, E2 gene plays a key role in multiple processes such as viral DNA replication and transcription. A methylation analysis study on the E2-binding site within LCR on epithelial cervical cancer cell line from HPV-16-infected patient was done, and it was demonstrated that poorly differentiated basal cells were hypermethylated and that particular region of E2-binding site was hypomethylated [88]. Thus, the change of methylation status of viral genome during its life cycle could be helpful in detecting a novel means to modulate functioning of E2 to inhibit its progression.

Apoptosis-related genes:The study of these types of genes being affected by the methylation in cervical cancer is very less. The decoy receptors, DcR1 and DcR2, could serve as the easy target for the abnormal methylation that could lead to their silencing and losing their function [89]. DcR genes are the members of Tumour Necrosis Factors (TNFs) which include, Fas, TNFR1 and decoy receptors for TRAIL. DcR1 and DcR2 are structurally related to the death inducing decoy receptors DR4 and DR5. DcR1 and DcR2 are postulated to serve as oncogenes due to their anti-apoptotic effects. In case of cervical cancer, there are number of cases that have shown the downregulation of decoy receptor expression by methylating DcR1 or DcR2 to obtain the advantage of growth [90, 91].

Apart from TNFs, the expression of hTERT in cervical cancer has been analyzed and 80–100% showed hTERT mRNA expression [92]. hTERT promoter has a high GC content with CpG island that could be affected by the methylation in regulating its expression. Hypermethylation leads to decrement in the gene expression. More research related to this study is awaited for the future.

Tumour suppressor genes:There are several hypermethylated genes observed in invasive cancers with specific functions that get either silenced or diminished (Table 2). TSLC1 is the gene that code for Ig like intercellular adhesion molecule that is able to mediate the calcium-independent interactions of Ca2. It was first identified in lung cancer, and the reason of its silencing was derived from either the loss of heterozygosity or promoter hypermethylation. The effect of this gene in suppressing cervical cancer was demonstrated by the study related to transfection of TSLC1 cDNA to SiHa cells. It showed reduction in anchorage-independent growth and able to generate less tumours in nude mice. The cervical lesions are accompanied by the expression loss of this tumour suppressor gene as in a case study, it was observed to show 58–65% increment in methylation rate in invasive tumours.

TSGs with rate of hypermethylationFunctions that get silenced or diminished
hTERT (57%)apoptosis
P16 (8–42%)Cell cycle
E-cadherin (28–81%)WNT pathway
MGMT (5–81%)DNA repair
BRAC1 (6.1%)FA-BRAC pathway
TSLC1 (58–65%)Tumour Suppressor
RASSF1A(0–45%)Negative Ras effect
RAR beta (33–66%)Cell differentiation
TIMP2/TIMP3 (47%)Tissue inhibitor

Table 2.

Hypermethylated genes silenced or diminished by various pathways

For the regulation of epithelial cell differentiation, retinoic acid is essential which is mediated by the RA-binding nuclear receptors. The target genes transcriptions by ligand-activated receptors are induced by the binding of RA responsive elements in promoter regions. RAR beta gene is one of those target genes that encode for tumour suppression. In many tumour cell lines and human tumours in primary stages, the complete or partial inhibition of gene expression has been observed [93]. The hypermethylation of promoter in colon and breast cancer leading to inhibition of RAR beta 2 inhibition has been observed. The retinoic acid inhibits the human keratinocyte transcription by HPV 16 that leads to regression of cancer [94]. The methylation rate of RAR beta 2 gene has been observed to show the increment from 33 to 63% in invasive cancers [95].

Histone acetylation:The regulation of gene transcription is majorly performed by the balance between histone deacetylases and histone acetyl transferase activity. Thus, the proper balance should be maintained in order to check the cell proliferation. HPV has E6 and E7 oncoproteins that are responsible to cause disturbance in the cell growth and proliferation. The E7 protein binds to HDACs and forms Mi2beta, an intermediary protein from nucleosome remodelling and histone deacetylation (NURD) complex that could modify the structure of chromatin. This modification is done by the nucleosome repositioning and histone deacetylation. Any mutation to E7 abolishes its binding to HDAC1 that results in loss of E7 to transform rodent fibroblast. In cervical cancer, phosphorylated and acetylated forms of H3 in the smears have shown the association of its modification with the progression of lesions from CNI to CNIII [96].

15. Current treatment and diagnosis

Cancer is caused by damage or mutations in the genetic material of the cells as a result of environmental or hereditary factors. Anti-cancer drugs (chemotherapy, hormone therapy and biological therapies) are the treatment of choice for metastatic tumours, while surgery and radiation are the primary treatments for local and non-metastatic cancers. Chemotherapy works by preventing malignant cells from dividing quickly, but it also affects normal cells with fast proliferation rates, such as hair follicles, bone marrow and gastrointestinal tract cells, resulting in chemotherapy's typical side effects.

There is a growing need for new effective targeted treatments based on the molecular biology of tumour cells due to the indiscriminate destruction of normal cells, the toxic side effects of conventional chemotherapy and the emergence of multidrug resistance.

During the past few years, FDA-approved targeted cancer drugs have become increasingly popular, causing cancer cells to die via apoptosis or by stimulating the immune system. These novel targeted therapies are gaining momentum as indicated by the growing number of cancer drugs approved by the FDA.

There are a variety of cancer treatments available. Treatment options will vary based on the type of cancer that an individual has and how far it has progressed.

Some cancer patients will just require one treatment. Most people, however, receive a combination of treatments, such as surgery along with chemotherapy and radiation. When it comes to cancer treatment, there is a lot to learn and consider.

16. Cancer treatment biomarker testing

Biomarker testing is a method of looking for cancer-related genes, proteins and other chemicals (also known as biomarkers or tumour markers). Biomarker testing can assist an individual or doctor in determining the best cancer treatment option.

16.1 Chemotherapy

Chemotherapy is a cancer treatment that involves the administration of chemicals to kill cancer cells. Chemotherapy is a cancer treatment that is used in conjunction with other cancer treatments. It has negative effects and is used to fight cancer.

16.2 Hormone therapy

Hormone therapy is a type of treatment that slows or stops the progression of tumours that use hormones to grow, such as breast and prostate cancer.

16.3 Hyperthermia

Hyperthermia is a method of treatment in which bodily tissue is heated to temperatures as high as 113 degrees Fahrenheit in order to destroy and kill cancer cells while causing little or no injury to healthy tissue. Hyperthermia is used to treat different types of malignancies and precancers.

16.4 Immunotherapy

Immunotherapy is a cancer treatment that boosts your immune system's ability to fight cancer. The different types of immunotherapy are used to treat cancer,

16.5 Photodynamic therapy (PDT)

To eliminate cancer and other aberrant cells, photodynamic treatment uses a medication that is activated by light. Individual gets know how it works, the types of tumours and precancers it treats and the benefits and cons of this treatment.

16.6 Radiation therapy

Radiation therapy is a cancer treatment that involves administering high doses of radiation to cancer cells in order to kill them and shrink tumours. Individual gets to know about the many forms of radiation, its side effects, which side effects one might have and more.

16.7 Stem cell transplant

Stem cell transplants are treatments that replace stem cells in persons whose blood cells have been damaged by severe doses of chemotherapy or radiation therapy. Although there are several types of transplants and their possible adverse effects, stem cell transplants are currently employed in cancer treatment.

16.8 Surgery

Surgery is a procedure in which a surgeon removes cancer from the body to treat cancer. There are various ways in which surgery is used to treat cancer.

16.9 Targeted therapy

Targeted therapy is a cancer treatment that focuses on the modifications that help cancer cells grow, divide and spread. Individual can learn how therapy works against cancer and how to avoid the most common side effects.

17. miRNA as a diagnostic biomarker

The study of miRNA expression levels in tumours could aid in the identification of tumour types and subtypes, as well as the prediction of their characteristics. Several studies have proven that miRNAs can be used as prognostic and/or diagnostic tools in various malignancies. The study of miRNA expression levels in tumours could aid in the identification of tumour types and subtypes, as well as the prediction of their characteristics.

Lu and colleagues investigated the relationship between miRNA expression profiles and developmental origin in 334 samples from multiple human cancers. They found that miRNA expression profiles correlate with development of cancer tissues [97].

Cancers such as breast, colorectal, prostate and colorectal occur frequently as a consequence of incorrect expression of genes such as ANRIL, HOTAIR, KCNQ1OT1 and XIST 16.

18. The epigenetic changes in cancer diagnosis and treatment

DNA methylation and histone modifications are significant epigenetic processes of gene regulation that play important roles in tumour initiation and development, both individually and cooperatively. In prostate cancer, abnormal epigenetic processes such as DNA hypo- and hypermethylation, as well as altered histone acetylation, have been found, affecting a large number of genes. Although the number of abnormally epigenetically regulated genes continues to grow, only a few genes have shown promise as potential tumour biomarkers for prostate cancer early detection and risk assessment. To detect prostate cancer-specific epigenetic fingerprints, large-scale screening of aberrant epigenetic processes such as DNA hypermethylation is required [98]. In human malignancies, DNA methylation is the epigenetic mark that has been examined the most. In 1983, cancer-related DNA methylation was discovered. DNA methylation inhibitors were clinically used to treat a range of cancers within 30 years of their discovery, emphasizing the importance of the epigenetic basis of cancer. Histone alterations, nucleosome remodelling and microRNA (miRNA)-mediated gene regulation are all important in tumour development. In all stages of lung cancer, including start, development and metastasis, distinct chromatin changes occur. As a result, stage-specific epigenetic modifications can be used as powerful and reliable methods for lung cancer early detection and patient prognosis monitoring. Furthermore, chromatin modifiers are interesting targets for the development of more effective therapeutic techniques against epigenetic alterations since they are dynamic and reversible [99].

19. Phytochemicals involved in cancer treatment

Vinca alkaloids, taxane diterpenoids, camptothecin derivatives and epipodophyllotoxin are the four principal types of clinically employed plant-derived anticancer agents. Other plant-derived anticancer drugs, such as combretastatins, homoharringtonine (omacetaxine mepesuccinate, cephalotaxine alkaloid) and ingenol mebutate, are employed in addition to these phytochemical groups. Poor water solubility and considerable hazardous side effects are still key concerns, so researchers are currently focusing their efforts on reducing their impact. Several analogues and prodrugs have been created in this context, as well as approaches to improve aqueous solubility and tumour selectivity. Below is a brief summary of a few phytochemicals that are employed in cancer treatment.

19.1 Vinca alkaloids

Vinca alkaloids are a class of medications derived from Catharanthus roseus, a pink periwinkle plant. The Vinca alkaloids cause cytotoxicity by binding to tubulin at a different position than the taxanes, preventing microtubule polymerization and assembly, resulting in metaphase arrest and cell death. The vinca alkaloids influence both malignant and non-malignant cells in the non-mitotic cell cycle because microtubules are involved in various other cellular processes such as cell shape preservation, motility and transfer between organelles. The two naturally separated alkaloids vinblastine and vincristine have been utilized in clinical oncology for nearly 50 years. These two alkaloids have a number of semisynthetic equivalents that have been produced. Vinorelbine and vindesine are two semisynthetic analogues that have been approved for use in clinical trials. These drugs are commonly used in combination chemotherapy to treat a range of cancers [100].

19.2 Taxanes

Taxanes are anticancer compounds that were first discovered in the bark of the Yew tree. Taxanes inhibit cancer growth by stabilizing microtubules, causing cell cycle arrest and abnormal mitosis. Paclitaxel, a natural substance derived from the bark and leaves of Taxus brevifolia and docetaxel, a semi-synthetic derivative, are largely used in the treatment of breast, ovarian, pancreatic, prostate and lung cancers. A number of semisynthetic compounds with better cytotoxicity in resistant tumours, reduced toxicity and improved solubility have been produced. Cabazitaxel, a second-generation docetaxel derivative, for example, has cytotoxic effectiveness against a variety of docetaxel-resistant cancers while posing a lower overall toxicity risk [101, 102]. Cabazitaxel also has the ability to permeate the blood-brain barrier in vivo, which is something that other taxanes can't do. Larotaxel, milataxel, ortataxel and tesetaxel are some of the paclitaxel analogues now being studied in clinical trials.

19.3 Camptothecins

Camptothecin is a quinolone alkaloid discovered from Camptotheca acuminata, a Chinese tree. Camptothecin forms a compound with type I DNA topoisomerase, which prevents DNA cleavage and religation, resulting in a DNA double-strand break and cytotoxicity [103]. Currently, the two FDA-approved semi-synthetic camptothecin derivatives that are therapeutically active and less toxic than the parent molecule are irinotecan and topotecan. Irinotecan is a drug that is used to treat advanced malignancies of the gut and rectum. Topotecan, on the other hand, has been approved for the treatment of ovarian cancer, small-cell lung cancer and cervical cancer.

19.4 Podophyllotoxins

Podophyllotoxin is a naturally occurring toxin found in the plants Podophyllum peltatum and Podophyllum emodi(Berberidaceae). Podophyllotoxin binds to tubulin in a reversible manner, whereas its main derivatives etoposide and teniposide inhibit topoisomerase II, causing DNA cleavage by topoisomerase II. Furthermore, podophyllotoxin has anti-multidrug resistance (MDR) efficacy against a variety of drug-resistant tumour cells. CIP-36, a podophyllotoxin derivative, has been found to overcome the MDR of the adriamycin-resistant K562/ADR human leukaemic cell line by modulating topoisomerase-IIa activity [104]. CIP-36, on the other hand, failed in clinical testing due to ineffectiveness and unacceptable toxicity.

19.5 Reversal of hypermethylation

Lee et al. also discovered that EGCG and similar substances inhibit DNMT and reverse hypermethylation [105, 106]. They discovered that EGCG inhibited DNMT activity directly and partially altered the methylation state of RAR-ß. Other catechol polyphenols inhibited DNMT indirectly by methylating S-adenosyl-L-methionine (SAM) and converting it to S-adenosyl-L-homocysteine (SAH), a potent DNMT inhibitor. In breast cancer cell lines, caffeic acid and chlorogenic acid partially prevented methylation of the RAR-ß gene promoter region [106]. The effect of EGCG, however, may be gene or cell line specific, and it was not as strong as 5-aza-2′-deoxycytidine (DAC) [107].

Some of the methylation-silenced genes were discovered to be demethylated and reactivated by isoflavones, with genistein being the most effective isoflavone from soy [108]. Genistein (20–50 mmol/L) suppressed DNMT activity in a dose-dependent manner, with competitive and noncompetitive inhibition of the substrate. Biochanin A and daidzein, two other isoflavones, were less effective in inhibiting DNMT activity, reactivating RAR- and stopping cancer cell growth. Although genistein was a weaker DNMT inhibitor than EGCG, it was equally as effective or even more effective than EGCG in demethylating hypermethylated genes and reactivating their expression.

When KYSE 510 cells were treated with 2 M genistein and 5 M EGCG, or 5 M genistein and 10 M EGCG, the expression of p16 was apparently increased compared with genistein or EGCG alone. The synergistic activity of these two drugs raised the levels of acetylated histone H3 and H4 in KYSE 510 cells when they were treated with genistein (5 M) for 5 days and subsequently with the HDAC inhibitor trichostatin (0.5 M) for 3 hours. Genistein and trichostatin increase the binding of acetylated H3 and H4 to the promoter region of RAR- and MGMT in a synergistic manner, according to a chromatin immunoprecipitation (ChIP) test. Other dietary components that inhibit DNMT include quercetin, luteolin, and hydroxycinnamic acid.

20. Conclusion

In the reports of 2018, 18.1 million new cancer cases were detected with 53% mortality rate. This disease is more prevalent in males as compared in females with ratio of 1.17. There are about more than 100 types of cancers that have been reported. Cancer is the disease that is caused by the genetic and the epigenetic factors that cause alterations in the gene functions. These genes are known as tumour suppressor genes which perform crucial function in inhibiting the invasion of tumour and its progression in the cell. The epigenetic factors such as hypomethylation in oncogenes, hypermethylation of tumour suppressor genes and the direct mutagenesis. These epigenetic factors are responsible for the tumorigenesis, and they are reversible in nature which makes them different from the genetic mutations. The new need of targeted molecular therapy is required on tumour cells as they are different from the normal cells, but the old treatments of cancer by radiotherapy and chemotherapy have the toxic side effect with less survival rate. The reversal could be done by the phytochemicals. There are various phytochemicals known that have shown the apoptosis in cancer cells such as alkaloid, taxane, camptothecins and podophyllotxins. These phytochemicals such as EGCG have been observed to inhibit the activity of DNMT1 directly and the partial activity of the rar-beta gene. In some cases, isoflavones have been observed to demethylate and reactivate the suppressor genes. The phytochemicals could be used as a drug to treat and prevent cancer by reversing the promoter hypermethylated genes that lead to loss of vital function performing genes such as transcriptional factors. These epigenetic factors could be used in future research to identify, diagnose, prevent and treat cancer as they could serve as one of the primary hallmarks of cancer and the reversal could lead to early prevention of cancer.

21. Future prospects

The epigenetic factors involved in the cancer could be either aberrant methylation (hypomethylation or hypermethylation) or direct mutagenesis of the vital genes. The genes that play a vital role in suppression of tumorigenesis, when altered by the epigenetic factors, lose their function such as gatekeeper genes or transcription factors. These epigenetic factors could be used as primary hallmark for the early detection of cancer. The DNA aberrant methylation could be reversed by the phytochemicals and be used in early-stage treatment of cancer. Thus, these epigenetic factors that lead to cancer and tumorigenesis can play a vital role in early diagnosis, prevention and treatment of this disease.

References

  1. 1. Hajdu SI. A note from history: Landmarks in history of cancer, part 1. Cancer. 2011;117(5):1097-1102
  2. 2. Paul of Aegina, 7th Century AD, quoted in Moss, Ralph W. “Galen on Cancer.” Cancer Decisions. Archived from the original on 16 July 2011. Referenced from Michael Shimkin, Contrary to Nature, Washington, DC: Superintendent of Document, DHEW Publication No. (NIH). 2004. 79–720, p. 35
  3. 3. Hajdu SI. A note from history: Landmarks in history of cancer, part 2. Cancer. 2011;117(12):2811-2820
  4. 4. Yalom M. A History of the Breast. 1st ed. New York: Ballantine Books; 1998
  5. 5. “Cancer”. World Health Organization. 12 September 2018. Retrieved 19 December 2018
  6. 6. Cancer – Signs and symptoms. NHS Choices. Archived from the original on 8 June 2014. Retrieved 10 June 2014
  7. 7. “Defining Cancer”. National Cancer Institute. 17 September 2007. Retrieved 28 March 2018
  8. 8. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharmaceutical Research. 2008;25(9):2097-2116
  9. 9. World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 1.1. ISBN: 978-92-832-0429-9. Archived from the original on 12 July 2017
  10. 10. “Heredity and Cancer”. American Cancer Society. Archived from the original on 2 August 2013. Retrieved 22 July 2013
  11. 11. Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, et al. American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: Reducing the risk of cancer with healthy food choices and physical activity. CA: A Cancer Journal for Clinicians Cancer. 2012;62(1):30-67
  12. 12. Parkin DM, Boyd L, Walker LC (December 2011). “16. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010”. British Journal of Cancer 105 Suppl 2: S77–S81
  13. 13. World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 4.7. ISBN: 978-92-832-0429-9. Archived from the original on 12 July 2017
  14. 14. “SEER Stat Fact Sheets: All Cancer Sites.” National Cancer Institute. Archived from the original on 26 September 2010. Retrieved 18 June 2014
  15. 15. Islami F, Goding Sauer A, Miller KD, Siegel RL, Fedewa SA, Jacobs EJ, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA: A Cancer Journal for Clinicians. 2018;68(1):31-54
  16. 16. Cohen S, Murphy ML, Prather AA. Ten surprising facts about stressful life events and disease risk. Annual Review of Psychology. 2019;70:577-597
  17. 17. Heikkilä K, Nyberg ST, Theorell T, Fransson EI, Alfredsson L, Bjorner JB, et al. “Work stress and risk of cancer: Meta-analysis of 5700 incident cancer events in 116,000 European men and women”. 2013
  18. 18. “Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018” (PDF)
  19. 19. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA: A Cancer Journal for Clinicians. 2014;64(2):83-103
  20. 20. Fathallah-Shaykh HM, Zhao LJ, Mickey B, Kafrouni AI. Molecular advances to treat cancer of the brain. Expert Opinion on Investigational Drugs. 2000;9(6):1207-1215
  21. 21. Smalley M, Ashworth A. Stem cells and breast cancer: A field in transit. Nature Reviews. Cancer. 2003;3(11):832-844
  22. 22. Vargo-Gogola T, Rosen JM. Modelling breast cancer: One size does not fitall. Nature Reviews. Cancer. 2007;7(9):659-672
  23. 23. Burghardt E. Early histological diagnosis of cervical cancer. Major Problems in Obstetrics and Gynecology. 1973;6:1-401
  24. 24. Hofmeister S. Cervical cancer screening: How our approach may change. The Journal of Family Practice. 2016;65(8):551-553
  25. 25. Marley AR, Nan H. Epidemiology of colorectal cancer. International Journal of Molecular Epidemiology and Genetics. 2016;7(3):10514
  26. 26. Enzinger PC, Mayer RJ. Esophageal cancer. The New England Journal of Medicine. 2003;349(23):2241-2252
  27. 27. Napier KJ, Scheerer M, Misra S. Esophageal cancer: A review of epidemiology, pathogenesis, staging workup and treatment modalities. World Journal of Gastrointestinal Oncology. 2014;6(5):112-120
  28. 28. Van der Schroeff MP, Baatenburg de Jong RJ. Staging and prognosis in head and neck cancer. Oral Oncology. 2009;45(4–5):356-360
  29. 29. Popescu B, Ene P, Bertesteanu SV, et al. Methods of investigating metastatic lymph nodes in head and neck cancer. Maedica. 2013;8(4):384-387
  30. 30. Glazer CA, Chang SS, Ha PK, et al. Applying the molecular biology and epigenetics of head and neck cancer in everyday clinical practice. Oral Oncology. 2009;45(4–5):440-446
  31. 31. Báez A. Genetic and environmental factors in head and neck cancer genesis. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews. 2008;26(2):174-200
  32. 32. Hui JY. Epidemiology and etiology of sarcomas. Surgical Clinical of North America. 2016;96(5):901-914; Cairns P. Renal cell carcinoma. Cancer Biomarkers 2010;9(1–6):461–73
  33. 33. Sudarshan S, Linehan WM. Genetic basis of cancer of the kidney. Seminars in Oncology. 2006;33(5):544-551
  34. 34. Sidana A, Srinivasan R. Therapeutic strategies for hereditary kidney cancer. Current Oncology Reports. 2016;18(8):50
  35. 35. Zhi XS, Xiong J, Zi XY, Hu YP. The potential role of liver stem cells in initiation of primary liver cancer. Hepatology International. 2016;10(6):893-901
  36. 36. Tsukuma H, Tanaka H, Ajiki W, Oshima A. Liver cancer and its prevention. Asian Pacific Journal of Cancer Prevention. 2005;6(3):244-250
  37. 37. Sánchez-Aguilera A, Méndez-Ferrer S. The hematopoietic stem-cell niche in health and leukemia. Cellular and Molecular Life Sciences. 2016;74(4):579-590
  38. 38. Knudson AG. Two genetic hits (more or less) to cancer. Nature Reviews. Cancer. 2001;1:157-162
  39. 39. Baylin SB, Jones PA. A decade of exploring the cancer epigenome—Biological and translational implications. Nature Reviews. Cancer. 2011;11:726-734
  40. 40. You JS, Jones PA. Cancer genetics and epigenetics: Two sides of the same coin? Cancer Cell. 2012;22:9-20
  41. 41. Reddy KL, Feinberg AP. Higher order chromatin organization in cancer. Seminars in Cancer Biology. 2013;23:109-115
  42. 42. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH Roadmap epigenomics mapping consortium. Nature Biotechnology. 2010;28:1045-1048
  43. 43. Zheng L, Dai H, Zhou M, Li X, Liu C, Guo Z, et al. Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression. Nature Communications. 2012;3:815
  44. 44. Jones PA, Laird PW. Cancer epigenetics comes of age. Nature Genetics. 1999;21:163-167
  45. 45. Ehrlich M, Lacey M. DNA hypomethylation and hemimethylation in cancer. Advances in Experimental Medicine and Biology. 2013;754:31-56
  46. 46. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998;395:89-93
  47. 47. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Research. 1994;54:4855-4878
  48. 48. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683-692
  49. 49. Kulis M, Heath S, Bibikova M, Queiros AC, Navarro A, Clot G, et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nature Genetics. 2012;44:1236-1242
  50. 50. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457-463
  51. 51. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: Epigenetics joins genetics. Trends in Genetics. 2000;16:168-174
  52. 52. Jones PA, Laird PW. Cancer epigenetics comes of age. Nature Genetics. 1999;21:163-167
  53. 53. Costello JF, Fruhwald MC, Smiraglia DJ, et al. Aberrant CpG-island methylation has non-random and tumor-type-specific patterns. Nature Genetics. 2000;24:132-138
  54. 54. Toyota M, Ho C, Ahuja N, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Research. 1999;59:2307-2312
  55. 55. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proceedings of the National Academy of Science USA. 1999;96:8681-8686
  56. 56. Baylin SB, Belinsky SA, Herman JG. Aberrant methylation of gene promoters in cancer—concepts, misconcepts and promise. Journal of the National Cancer Institute. 2000;92:1460-1461
  57. 57. Makos M, Nelkin BD, Lerman MI, Latif F, Zbar B, Baylin SB. Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer. Proceedings of the National Academy of Science USA. 1992;89:1929-1933
  58. 58. Wales MM, Biel MA, el Deiry W, et al. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature Medicine. 1995;1:570-577
  59. 59. Makos M, Nelkin BD, Reiter RE, et al. Regional DNA hypermethylation at D17S5 precedes 17p structural changes in the progression of renal tumors. Cancer Research. 1993;53:2719-2722
  60. 60. Guerardel C, Deltour S, Pinte S, et al. Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53. The Journal of Biological Chemistry. 2001;275:307-308
  61. 61. Carter MG, Johns MA, Zeng X, et al. Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller–Dieker syndrome. Human Molecular Genetics. 2000;9:413-419
  62. 62. Foster SA, Wong DJ, Barrett MT, Galloway DA. Inactivation of p16 in human mammary epithelial cells by CpG island methylation. Molecular and Cellular Biology. 1998;18:1793-1801
  63. 63. Loughran O, Malliri A, Owens D, et al. Association of CDKN2A/p16INK4A with human head and neck keratinocyte replicative senescence: Relationship of dysfunction to immortality and neoplasia. Oncogene. 1996;13:561-568
  64. 64. Wong DJ, Barrett MT, Stoger R, Emond MJ, Reid BJ. p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Research. 1997;57:2619-2622
  65. 65. Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proceedings of the National Academy of Science USA. 1998;95:11891-11896
  66. 66. Kinzler KW, Vogelstein B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature. 1997;386:761-763
  67. 67. Graff JR, Gabrielson E, Fujii H, Baylin SB, Herman JG. Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. The Journal of Biological Chemistry. 2000;275:2727-2732
  68. 68. Pietenpol JA, Bohlander SK, Sato Y, et al. Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. Cancer Research. 1995;55:1206-1210
  69. 69. Hsieh CL. Dependence of transcriptional repression on CpG methylation density. Molecular and Cellular Biology. 1994;14:5487-5494
  70. 70. Vertino PM, Yen RW, Gao J, Baylin SB. De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. Molecular and Cellular Biology. 1996;16:4555-4565
  71. 71. Myohanen SK, Baylin SB, Herman JG. Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. Cancer Research. 1998;58:591-593
  72. 72. Mareel M, Bracke M, Van Roy F. CaNcer metastasis: Negative regulation by an invasion-suppressor complex. Cancer Detection and Prevention. 1995;19:451-464
  73. 73. Moll R, Mitze M, Frixen UH, Birchmeier W. Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. The American Journal of Pathology. 1993;143:1731-1742
  74. 74. Siitonen SM, Kononen JT, Helin HJ, Rantala IS, Holli KA, Isola JJ. Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. American Journal of Clinical Pathology. 1996;105:394-402
  75. 75. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genetics. 1999;21:103-107
  76. 76. Cairns J. Mutation selection and the natural history of cancer. Nature. 1975;255:197-200
  77. 77. Fearon ER, Vogelstein, 8. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759-767
  78. 78. Harris H. The analysis of malignancy by cell fusion: The position in 1988. Cancer Research. 1988;48:3302-3306
  79. 79. Stanbridge EJ, Ceredig R. Growth-regulatory control of human cell hybrids in nude mice. Cancer Research. 1981;47:573-580
  80. 80. “Tumor Suppressor (TS) Genes and the Two-Hit Hypothesis | Learn Science at Scitable”.www.nature.com. Retrieved 2019-10-06
  81. 81. Harris CC. Structure and function of p53 tumor suppressor gene: Clues for rational cancer therapeutic strategies. Journal of the National Cancer Institute. 1996;88(20):1442-1455. DOI: 10.1093/jnci/88.20.1442. PMID 8841019
  82. 82. “BCL2 (B-Cell Leukemia/Lymphoma 2).”atlasgeneticsoncology.org. Retrieved 2019-11-21
  83. 83. Antequera F, Bird A. CpG islands. EXS. 1993;64:169-185
  84. 84. Verma M. Viral genes and methylation. Annals of the New York Academy of Sciences. 2003;983:170-180
  85. 85. Tao Q, Huang H, Geiman TM, Lim CY, Fu L, Qiu GH, et al. Defective de novo methylation of viral and cellular DNA sequences in ICF syndrome cells. Human Molecular Genetics. 2002;11:2091-2102. DOI: 10.1093/hmg/11.18.2091
  86. 86. Tao Q, Robertson KD. Stealth technology: How Epstein-Barr virus utilizes DNA methylation to cloak itself from immune detection. Clinical Immunology. 2003;109:53-63. DOI: 10.1016/S1521-6616(03)00198-0
  87. 87. Rosl F, Arab A, Klevenz B, zur Hausen H. The effect of DNA methylation on gene regulation of human papillomaviruses. The Journal of General Virology. 1993;74:791-801
  88. 88. Kalantari M, Calleja-Macías IE, Tewari D, Hagmar B, Lie K, Barrera-Saldaña HA, et al. Conserved methylation patterns of human papillomavirus type 16 DNA in asymptomatic infection and cervical neoplasia. Journal of Virology. 2004;78:12762-12772
  89. 89. Thain A, Jenkins O, Clarke AR, Gaston K. CpG methylation directly inhibits binding of the human papillomavirus type 16 E2 protein to specific DNA sequences. Journal of Virology. 1996;70:7233-7235
  90. 90. Van Noesel MM, van Bezouw S, Salomons GS, Voute PA, Pieters R, Baylin SB, et al. Tumor-specific down-regulation of the tumor necrosis factor-related apoptosis-inducing ligand decoy receptors DcR1 and DcR2 is associated with dense promoter hypermethylation. Cancer Research. 2002;62:2157-2161
  91. 91. Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Current Opinion in Cell Biology. 1999;11:255-260
  92. 92. Ozoren N, El-Deiry WS. Cell surface death receptor signaling in normal and cancer cells. Seminars in Cancer Biology. 2003;13:135-147
  93. 93. Nakano N, Watney E, McDougall JK. Telomerase activity and expression of telomerase RNA component and telomerase catalytic subunit gene in cervical cancer. The American Journal of Pathology. 1998;153:857-864
  94. 94. Chambon P. The retinoid signaling pathway: Molecular and genetic analyses. Seminars in Cell Biology. 1994;5:115-125
  95. 95. Meyskens FL, Surwit E, Moon TE, Childers JM, Davis JR, Dorr RT, et al. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans retinoic acid: A randomized trial. Journal of the National Cancer Institute. 1994;86:539-543
  96. 96. Vanova T, Petrenko A, Gritsko T, Vinokourova S, Eshilev E, Kobzeva V, et al. Methylation and silencing of the retinoic acid receptor-beta 2 gene in cervical cancer. BMC Cancer. 2002;2:4
  97. 97. Visone R, Croce CM. MiRNAs and cancer. The American Journal of Pathology. 2009;174:1131-1138
  98. 98. Li L-C, Carroll PR, Dahiya R. Epigenetic changes in prostate cancer: Implication for diagnosis and treatment. National Cancer Institute. 2005;97(2):103-115
  99. 99. Mehta A, Dobersch S, Romero-Olmedo AJ, Barreto G. Epigenetics in lung cancer diagnosis and therapy. Cancer Metastasis Review. 2015;34(2):229-241
  100. 100. Martino E, Casamassima G, Castiglione S, Cellupica E, Pantalone S, Papagni F, et al. Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead. Bioorganic & Medicinal Chemistry Letters. 2018;28(17):2816-2826. DOI: 10.1016/j.bmcl.2018.06.044
  101. 101. Kotsakis A, Matikas A, Koinis F, Kentepozidis N, Varthalitis II, Karavassilis V, et al. A multicentre phase II trial of cabazitaxel in patients with advanced non-small-cell lung cancer progressing after docetaxel-based chemotherapy. British Journal of Cancer. 2016;115(7):784-788. DOI: 10.1038/bjc.2016.281
  102. 102. Oudard S, Fizazi K, Sengelov L, Daugaard G, Saad F, Hansen S, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III trial-firstana. Journal of Clinical Oncology. 2017;35(28):3189-3197. DOI: 10.1200/JCO.2016.72.1068
  103. 103. Hertzberg RP, Caranfa MJ, Hecht SM. On the mechanism of topoisomerase, I inhibition by camptothecin: Evidence for binding to an enzyme-DNA complex. Biochemistry. 1989;28(11):4629-4638. DOI: 10.1021/bi00437a018
  104. 104. Cao B, Chen H, Gao Y, Niu C, Zhang Y, Li L. CIP-36, a novel topoisomerase II-targeting agent, induces the apoptosis of multidrug-resistant cancer cells in vitro. International Journal of Molecular Medicine. 2015;35(3):771-776. DOI: 10.3892/ijmm.2015.2068
  105. 105. Lee WJ, Shim JY, Zhu BT. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Molecular Pharmacology. 2005;68:1018-1030
  106. 106. Lee WJ, Zhu BT. Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. Carcinogenesis. 2006;27:269-277
  107. 107. Chuang JC, Yoo CB, Kwan JM, et al. Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2′-deoxycytidine. Molecular Cancer Therapeutics. 2005;4:1515-1520
  108. 108. Fang MZ, Chen D, Sun Y, Jin Z, Christman JK, Yang CS. Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clinical Cancer Research. 2005;11:7033-7041

Written By

Mehak Sharan, Runjhun Mathur, Niraj Kumar Jha, Khushboo Rana, Saurabh Kumar Jha and Abhimanyu Kumar Jha

Submitted: January 8th, 2022 Reviewed: February 16th, 2022 Published: May 5th, 2022