Cancer epigenetics

Source: Wikipedia, the free encyclopedia.

Cancer epigenetics is the study of

DNA binding proteins
. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

Epigenetics patterns in a normal and cancer cells
Epigenetic alterations in tumour progression

Mechanisms

DNA methylation

Main article: DNA methylation in cancer
A DNA molecule fragment that is methylated at two cytosines

In somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with high fidelity.

repeat sequences is often decreased.[11]

Hypermethylation of tumor suppressor gene promoter regions can result in silencing of those genes. This type of epigenetic mutation allows cells to grow and reproduce uncontrollably, leading to tumorigenesis.

MGMT, a DNA repair gene; APC, a cell cycle regulator; MLH1, a DNA-repair gene; and BRCA1, another DNA-repair gene.[10][12] Indeed, cancer cells can become addicted to the transcriptional silencing, due to promoter hypermethylation, of some key tumor suppressor genes, a process known as epigenetic addiction.[13]

Hypomethylation of CpG dinucleotides in other parts of the genome leads to

non-coding intergenic regions. Expression of some repetitive sequences and meiotic recombination at centromeres are repressed through methylation [19]

The entire genome of a cancerous cell contains significantly less

chromosome rearrangement, ultimately resulting in aneuploidy when the chromosomes fail to separate properly during mitosis.[14][15][16][17]

CpG island methylation is important in regulation of gene expression, yet cytosine methylation can lead directly to destabilizing genetic mutations and a precancerous cellular state. Methylated cytosines make

heterozygosity at tumor suppressor gene sites, these genes may become inactive. Single base pair mutations during replication can also have detrimental effects.[12]

Histone modification

DNA packaging
outside of the nucleosome. Certain histone modifying enzymes can add or remove functional groups to the histones, and these modifications influence the level of transcription of the genes wrapped around those histones and the level of DNA replication. Histone modification profiles of healthy and cancerous cells tend to differ.

In comparison to healthy cells, cancerous cells exhibit decreased monoacetylated and trimethylated forms of

SIRT1, an HDAC specific for H4K16.[10][24]

Other histone marks associated with

tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 (H3K4me3), and increased monomethylation of histone H3 Lysine 9 (H3K9me1) and trimethylation of histone H3 Lysine 27 (H3K27me3). These histone modifications can silence tumor suppressor genes despite the drop in methylation of the gene's CpG island (an event that normally activates genes).[25][26]

Some research has focused on blocking the action of BRD4 on acetylated histones, which has been shown to increase the expression of the Myc protein, implicated in several cancers. The development process of the drug to bind to BRD4 is noteworthy for the collaborative, open approach the team is taking.[27]

The tumor suppressor gene p53 regulates DNA repair and can induce apoptosis in dysregulated cells. E Soto-Reyes and F Recillas-Targa elucidated the importance of the CTCF protein in regulating p53 expression.[28] CTCF, or CCCTC binding factor, is a zinc finger protein that insulates the p53 promoter from accumulating repressive histone marks. In certain types of cancer cells, the CTCF protein does not bind normally, and the p53 promoter accumulates repressive histone marks, causing p53 expression to decrease.[28]

Mutations in the epigenetic machinery itself may occur as well, potentially responsible for the changing epigenetic profiles of cancerous cells. The

HDAC2, a histone deacetylase that acts on many histone-tail lysines, has been associated with cancers showing altered histone acetylation patterns.[30] These findings indicate a promising mechanism for altering epigenetic profiles through enzymatic inhibition or enhancement. A new emerging field that captures toxicological epigenetic changes as a result of the exposure to different compounds (drugs, food, and environment) is toxicoepigenetics. In this field, there is growing interest in mapping changes in histone modifications and their possible consequences.[31]

G2/M checkpoint, allowing time for DNA repair, or apoptosis may be initiated.[32]

MicroRNA gene silencing

In mammals,

ESR1, that are linked to breast cancer. DNA methylation, specifically hypermethylation, is one of the main ways that the miR-125b1 is epigenetically silenced. In patients with breast cancer, hypermethylation of CpG islands located proximal to the transcription start site was observed. Loss of CTCF binding and an increase in repressive histone marks, H3K9me3 and H3K27me3, correlates with DNA methylation and miR-125b1 silencing. Mechanistically, CTCF may function as a boundary element to stop the spread of DNA methylation. Results from experiments conducted by Soto-Reyes et al.[36] indicate a negative effect of methylation on the function and expression of miR-125b1. Therefore, they concluded that DNA methylation has a part in silencing the gene. Furthermore, some miRNA's are epigenetically silenced early on in breast cancer, and therefore these miRNA's could potentially be useful as tumor markers.[36] The epigenetic silencing of miRNA genes by aberrant DNA methylation is a frequent event in cancer cells; almost one third of miRNA promoters active in normal mammary cells were found hypermethylated in breast cancer cells - that is a several fold greater proportion than is usually observed for protein coding genes.[37]

See also:
Cancer biomarkers § Risk assessment

Metabolic recoding of epigenetics in cancer

Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. In order to satisfy the biosynthetic demands of cancer cells, metabolic pathways are altered by manipulating oncogenes and tumor suppressive genes concurrently.[38] The accumulation of certain metabolites in cancer can target epigenetic enzymes to globally alter the epigenetic landscape. Cancer-related metabolic changes lead to locus-specific recoding of epigenetic marks. Cancer epigenetics can be precisely reprogramed by cellular metabolism through 1) dose-responsive modulation of cancer epigenetics by metabolites; 2) sequence-specific recruitment of metabolic enzymes; and 3) targeting of epigenetic enzymes by nutritional signals.[38] In addition to modulating metabolic programming on a molecular level, there are microenvironmental factors that can influence and effect metabolic recoding. These influences include nutritional, inflammatory, and the immune response of malignant tissues.

MicroRNA and DNA repair

DNA damage appears to be the primary underlying cause of cancer.

mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage can also increase epigenetic alterations due to errors during DNA repair.[41][42] Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms
).

colon cancer cases.[43] However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important causal
factor for these cancers.

Over-expression of certain miRNAs may directly reduce expression of specific DNA repair proteins. Wan et al.[44] referred to 6 DNA repair genes that are directly targeted by the miRNAs indicated in parentheses: ATM (miR-421), RAD52 (miR-210, miR-373), RAD23B (miR-373), MSH2 (miR-21), BRCA1 (miR-182) and P53 (miR-504, miR-125b). More recently, Tessitore et al.[45] listed further DNA repair genes that are directly targeted by additional miRNAs, including ATM (miR-18a, miR-101), DNA-PK (miR-101), ATR (miR-185), Wip1 (miR-16), MLH1, MSH2 and MSH6 (miR-155), ERCC3 and ERCC4 (miR-192) and UNG2 (mir-16, miR-34c and miR-199a). Of these miRNAs, miR-16, miR-18a, miR-21, miR-34c, miR-125b, miR-101, miR-155, miR-182, miR-185 and miR-192 are among those identified by Schnekenburger and Diederich[46] as over-expressed in colon cancer through epigenetic hypomethylation. Over expression of any one of these miRNAs can cause reduced expression of its target DNA repair gene.

Up to 15% of the

epigenetic methylation of the CpG island of the MLH1 gene.[48]

In 28% of glioblastomas, the MGMT DNA repair protein is deficient but the MGMT promoter is not methylated.

MGMT
gene, which reduces protein expression of MGMT.

High mobility group A (HMGA) proteins, characterized by an AT-hook, are small, nonhistone, chromatin-associated proteins that can modulate transcription. MicroRNAs control the expression of HMGA proteins, and these proteins (HMGA1 and HMGA2) are architectural chromatin transcription-controlling elements. Palmieri et al.[51] showed that, in normal tissues, HGMA1 and HMGA2 genes are targeted (and thus strongly reduced in expression) by miR-15, miR-16, miR-26a, miR-196a2 and Let-7a.

HMGA expression is almost undetectable in differentiated adult tissues but is elevated in many cancers. HGMA proteins are polypeptides of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed

AT hooks, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinoma, show a strong increase of HMGA1a and HMGA1b proteins.[52] Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is not only associated with cancers, but that the HMGA1 gene can act as an oncogene to cause cancer.[53] Baldassarre et al.,[54]
showed that HMGA1 protein binds to the promoter region of DNA repair gene BRCA1 and inhibits BRCA1 promoter activity. They also showed that while only 11% of breast tumors had hypermethylation of the BRCA1 gene, 82% of aggressive breast cancers have low BRCA1 protein expression, and most of these reductions were due to chromatin remodeling by high levels of HMGA1 protein.

HMGA2 protein specifically targets the promoter of ERCC1, thus reducing expression of this DNA repair gene.[55] ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is unknown).[56]

Palmieri et al.[51] showed that each of the miRNAs that target HMGA genes are drastically reduced in almost all human pituitary adenomas studied, when compared with the normal pituitary gland. Consistent with the down-regulation of these HMGA-targeting miRNAs, an increase in the HMGA1 and HMGA2-specific mRNAs was observed. Three of these microRNAs (miR-16, miR-196a and Let-7a)[46][57] have methylated promoters and therefore low expression in colon cancer. For two of these, miR-15 and miR-16, the coding regions are epigenetically silenced in cancer due to histone deacetylase activity.[58] When these microRNAs are expressed at a low level, then HMGA1 and HMGA2 proteins are expressed at a high level. HMGA1 and HMGA2 target (reduce expression of) BRCA1 and ERCC1 DNA repair genes. Thus DNA repair can be reduced, likely contributing to cancer progression.[40]

DNA repair pathways

A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error prone microhomology-mediated end joining pathway with increased expression in various cancers.

The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes.[59] Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.

Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Two broad experimental survey articles[60][61] also document most of these epigenetic DNA repair deficiencies in cancers.

Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see translesion synthesis) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis.

The two gray-highlighted genes RAD51 and BRCA2, are required for homologous recombinational repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in the Wikipedia articles on RAD51 and BRCA2, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where RAD51 or BRCA2 are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis) could cause increased mutations and cancer, so that under-expression of RAD51 or BRCA2 would be carcinogenic in itself.

Cyan-highlighted genes are in the microhomology-mediated end joining (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5-25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway.[62] FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,[63] prostate,[64] stomach,[65][66] neuroblastomas,[67] pancreas,[68] and lung.[69] PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,[70] BRCA-mutated ovarian cancer,[71] and BRCA-mutated serous ovarian cancer.[72] Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in blue.

Frequencies of epimutations in DNA repair genes

Deficiencies in DNA repair proteins that function in accurate DNA repair pathways increase the risk of mutation. Mutation rates are strongly increased in cells with mutations in DNA mismatch repair[73][74] or in homologous recombinational repair (HRR).[75] Individuals with inherited mutations in any of 34 DNA repair genes are at increased risk of cancer (see DNA repair defects and increased cancer risk).

In sporadic cancers, a deficiency in DNA repair is occasionally found to be due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. For example, for 113 colorectal cancers examined in sequence, only four had a

MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[76] Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 protein was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[48] In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[47]

Epigenetic defects in DNA repair genes are frequent in cancers. In the table, multiple cancers were evaluated for reduced or absent expression of the DNA repair gene of interest, and the frequency shown is the frequency with which the cancers had an epigenetic deficiency of gene expression. Such epigenetic deficiencies likely arise early in carcinogenesis, since they are also frequently found (though at somewhat lower frequency) in the field defect surrounding the cancer from which the cancer likely arose (see Table).

Frequency of epigenetic reduction in DNA repair gene expression in sporadic cancers and in adjacent field defects
Cancer Gene Frequency in Cancer Frequency in Field Defect Ref.
Colorectal
MGMT
 46% 34% [77]
Colorectal MGMT 47% 11% [78]
Colorectal MGMT 70% 60% [79]
Colorectal MSH2 13% 5% [78]
Colorectal ERCC1 100% 40% [56]
Colorectal PMS2 88% 50% [56]
Colorectal XPF 55% 40% [56]
Head and Neck MGMT 54% 38% [80]
Head and Neck MLH1 33% 25% [81]
Head and Neck MLH1 31% 20% [82]
Stomach MGMT 88% 78% [83]
Stomach MLH1 73% 20% [84]
Stomach ERCC1 95-100% 14-65% [85]
Stomach PMS2 95-100% 14-60% [85]
Esophagus MLH1 77%–100% 23%–79% [86]

It appears that cancers may frequently be initiated by an epigenetic reduction in expression of one or more DNA repair enzymes. Reduced DNA repair likely allows accumulation of DNA damages. Error prone

epimutation
of the DNA repair gene may be carried along as a passenger when the cells with the selectively advantageous mutation are replicated. In the cells carrying both the epimutation of the DNA repair gene and the mutation with the selective advantage, further DNA damages will accumulate, and these could, in turn, give rise to further mutations with still greater selective advantages. Epigenetic defects in DNA repair may thus contribute to the characteristic high frequency of mutations in the genomes of cancers, and cause their carcinogenic progression.

Cancers have high levels of genome instability, associated with a high frequency of mutations. A high frequency of genomic mutations increases the likelihood of particular mutations occurring that activate oncogenes and inactivate tumor suppressor genes, leading to carcinogenesis. On the basis of whole genome sequencing, cancers are found to have thousands to hundreds of thousands of mutations in their whole genomes.[87] (Also see Mutation frequencies in cancers.) By comparison, the mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation.[88][89] In the protein coding regions of the genome, there are only about 0.35 mutations between parent/child generations (less than one mutated protein per generation).[90] Whole genome sequencing in blood cells for a pair of identical twin 100-year-old centenarians only found 8 somatic differences, though somatic variation occurring in less than 20% of blood cells would be undetected.[91]

While DNA damages may give rise to mutations through error prone translesion synthesis, DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes.[41][42][92][93] The DNA damages that accumulate due to epigenetic DNA repair defects can be a source of the increased epigenetic alterations found in many genes in cancers. In an early study, looking at a limited set of transcriptional promoters, Fernandez et al.[94] examined the DNA methylation profiles of 855 primary tumors. Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG sites evaluated) showed differential DNA methylation. Of these sites, 496 were hypermethylated (repressed) and 233 were hypomethylated (activated). Thus, there is a high level of epigenetic promoter methylation alterations in tumors. Some of these epigenetic alterations may contribute to cancer progression.

Epigenetic carcinogens

A variety of compounds are considered as epigenetic

mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol, arsenite, hexachlorobenzene, and nickel
compounds.

Many

5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development.[99] In rats, endocrine differences were observed in offspring of males exposed to morphine.[100] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.[101]

Cancer subtypes

Skin cancer

photocarcinogenesis which is associated to epigenetic alterations in DNA methylation, DNA methyltransferases, and histone acetylation.[102] These alterations are the consequence of deregulation of their corresponding enzymes. Several histone methyltransferases and demethylases are among these enzymes.[103]

Prostate cancer

Prostate cancer kills around 35,000 men yearly, and about 220,000 men are diagnosed with prostate cancer per year, in North America alone.[104] Prostate cancer is the second leading cause of cancer-caused fatalities in men, and within a man's lifetime, one in six men will have the disease.[104] Alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer, and have been seen in genes involved in hormonal response.[105] More than 90% of prostate cancers show gene silencing by CpG island hypermethylation of the GSTP1 gene promoter, which protects prostate cells from genomic damage that is caused by different oxidants or carcinogens.[106] Real-time methylation-specific polymerase chain reaction (PCR) suggests that many other genes are also hypermethylated.[106] Gene expression in the prostate may be modulated by nutrition and lifestyle changes.[107]

Cervical cancer

The second most common malignant tumor in women is invasive

CADM1.[108] Furthermore, 1/3 of CpG sites in mitochondrial DNA were associated with increased methylation in CIN3+.[108] Thus, a correlation exists between CIN3+ and increased methylation of CpG sites in the HPV16 L1 open reading frame.[108] This could be a potential biomarker for future screens of cancerous and precancerous cervical disease.[108]

Leukemia

Recent studies have shown that the

mixed-lineage leukemia (MLL) gene causes leukemia by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.[109] Mutations in MLL block the correct regulatory regions in leukemia associated translocations or insertions causing malignant transformation controlled by HOX genes.[110] This is what leads to the increase in white blood cells. Leukemia related genes are managed by the same pathways that control epigenetics, signaling transduction, transcriptional regulation, and energy metabolism. It was indicated that infections, electromagnetic fields and increased birth weight can contribute to being the causes of leukemia.[111]

Sarcoma

There are about 15,000 new cases of sarcoma in the US each year, and about 6,200 people were projected to die of sarcoma in the US in 2014.[112] Sarcomas comprise a large number of rare, histogenetically heterogeneous mesenchymal tumors that, for example, include chondrosarcoma, Ewing's sarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, synovial sarcoma, and (alveolar and embryonal) rhabdomyosarcoma. Several oncogenes and tumor suppressor genes are epigenetically altered in sarcomas. These include APC, CDKN1A, CDKN2A, CDKN2B, Ezrin, FGFR1, GADD45A, MGMT, STK3, STK4, PTEN, RASSF1A, WIF1, as well as several miRNAs.[113] Expression of epigenetic modifiers such as that of the BMI1 component of the PRC1 complex is deregulated in chondrosarcoma, Ewing's sarcoma, and osteosarcoma, and expression of the EZH2 component of the PRC2 complex is altered in Ewing's sarcoma and rhabdomyosarcoma. Similarly, expression of another epigenetic modifier, the LSD1 histone demethylase, is increased in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Drug targeting and inhibition of EZH2 in Ewing's sarcoma,[114] or of LSD1 in several sarcomas,[115] inhibits tumor cell growth in these sarcomas.

Lung Cancer

Lung cancer is the second most common type of cancer and leading cause of death in men and women in the United States, it is estimated that there is about 216,000 new cases and 160,000 deaths due to lung cancer.[116]

Initiation and progression of lung carcinoma is the result of the interaction between genetic, epigenetic and environmental factors. Most cases of lung cancer are because of genetic mutations in EGFR, KRAS, STK11 (also known as LKB1), TP53 (also known as p53), and CDKN2A (also known as p16 or INK4a)[117][118][119] with the most common type of lung cancer being an inactivation at p16. p16 is a tumor suppressor protein that occurs in mostly in humans the functional significance of the mutations was tested on many other species including mice, cats, dogs, monkeys and cows the identification of these multiple nonoverlapping clones was not entirely surprising since the reduced stringency hybridization of a zoo blot with the same probe also revealed 10-15 positive EcoRI fragments in all species tested.[120]

Identification methods

Previously, epigenetic profiles were limited to individual genes under scrutiny by a particular research team. Recently, however, scientists have been moving toward a more genomic approach to determine an entire genomic profile for cancerous versus healthy cells.[10]

Popular approaches for measuring CpG methylation in cells include:

Since bisulfite sequencing is considered the gold standard for measuring CpG methylation, when one of the other methods is used, results are usually confirmed using bisulfite sequencing[1]. Popular approaches for determining

histone modification profiles in cancerous versus healthy cells include:[10]

Diagnosis and prognosis

Researchers are hoping to identify specific epigenetic profiles of various types and subtypes of cancer with the goal of using these profiles as tools to diagnose individuals more specifically and accurately.

brain cancers.[17]
This type of knowledge can affect the way that doctors will diagnose and choose to treat their patients.

Another factor that will influence the treatment of patients is knowing how well they will respond to certain treatments. Personalized epigenomic profiles of cancerous cells can provide insight into this field. For example,

chemotherapeutic drugs act in order to disrupt DNA and cause cell death.[122][123][124][125]
Therefore, if the gene encoding MGMT in cancer cells is hypermethylated and in effect silenced or repressed, the chemotherapeutic drugs that act by methylating guanine will be more effective than in cancer cells that have a functional MGMT enzyme.

Epigenetic

CDH13 serves as the marker for increased risk of faster cancer relapse and higher death rate of patients.[126]

Treatment

decitabine

Epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones plays a role in the formation and progression of cancer.[127] Pharmaceuticals that reverse epigenetic changes might have a role in a variety of cancers.[105][127][128]

Recently, it is evidently known that associations between specific cancer histotypes and epigenetic changes can facilitate the development of novel epi-drugs.[129] Drug development has focused mainly on modifying DNA methyltransferase, histone acetyltransferase (HAT) and histone deacetylase (HDAC).[130]

Drugs that specifically target the inverted methylation pattern of cancerous cells include the

bone marrow stem cells.[12] These agents inhibit all three types of active DNA methyltransferases, and had been thought to be highly toxic, but proved to be effective when used in low dosage, reducing progression of myelodysplastic syndrome to leukemia.[136]

myeloma.[140]

Other pharmaceutical targets in research are histone lysine methyltransferases (KMT) and protein arginine methyltransferases (PRMT).[141] Preclinical study has suggested that lunasin may have potentially beneficial epigenetic effects.[142]

Epigenetic Therapy

Epigenetic therapy of cancer has shown to be a promising and possible treatment of cancerous cells. Epigenetic inactivation is an ideal target for cancerous cells because it targets genes imperative for controlling cell growth, specifically cancer cell growth. It is crucial for these genes to be reactivated in order to suppress tumor growth and sensitize the cells to cancer curing therapies.[143] Typical chemotherapy aims to kill and eliminate cancer cells in the body. Cancer initiated by genetic alterations of cells are typically permanent and nearly impossible to reverse, this differs from epigenetic cancer because the cancer causing epigenetic aberrations have the capability of being reversed, and the cells being returned to normal function. The ability for epigenetic mechanisms to be reversed is attributed to the fact that the coding of the genes being silenced through histone and DNA modification is not being altered.[144]

There are two primary types of epigenetic alterations in cancer cells, these are known as DNA methylation and Histone modification. It is the goal of epigenetic therapies to inhibit these alterations. DNA Methyltransferases (DNMTs) and Histone Deacetylases (HDAC) are the primary catalyzes of the epigenetic modifications of cancer cells.[145] The goal for epigenetic therapies is to repress this methylation and reverse these modifications in order to create a new epigenome where cancer cells no longer thrive and tumor suppression is the new function. Synthetic drugs are used as tools in epigenetic therapies due to their ability to inhibit enzymes causing histone modifications and DNA methylations. Combination therapy is one method of epigenetic therapy which involves the use of more than one synthetic drug, these drugs include a low dose DNMT inhibitor as well as an HDAC inhibitor. Together, these drugs are able to target the linkage between DNA methylation and Histone modification.[146]

The goal of epigenetic therapies for cancer in relation to DNA methylation is to both decrease the methylation of DNA and in turn decrease the silencing of genes related to tumor suppression.[147] The term associated with decreasing the methylation of DNA will be known as hypomethylation. The Food and Drug Administration (FDA) has currently approved one hypomethylating agent which, through the conduction of clinical trials, has shown promising results when utilized to treat patients with Myelodysplastic Syndrome (MDS).[148] This hypomethylating agent is known as the doozy analogue of 5-azacytidine and works to promote hypomethylation by targeting all DNA methyltransferases for degradation.[147]

See also

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  74. PMID 16728433
    .
  75. PMID 11850397
    .
  76. PMID 15888787
    .
  77. PMID 16174854
    .
  78. ^
    S2CID 8069716
    .
  79. S2CID 206950452
    .
  80. PMID 21147548
    .
  81. S2CID 8357370
    .
  82. PMID 21353335
    .
  83. PMID 19695681
    .
  84. PMID 23098428
    .
  85. ^
    S2CID 212622031
    .
  86. PMID 22808291
    .
  87. PMID 23178448
    .
  88. PMID 20220176
    .
  89. PMID 23001126
    .
  90. PMID 22345605
    .
  91. PMID 24182360
    .
  92. PMID 20550933
    .
  93. PMID 24137009
    .
  94. PMID 21613409
    .
  95. PMID 9434858
    .
  96. S2CID 25874971
    .
  97. S2CID 9014237
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  98. S2CID 2260876
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  99. ^ "Vidaza (azacitidine for injectable suspension) package insert" (PDF). Pharmion Corporation. U.S. Food and Drug Administration. 18 May 2004. Archived from the original (PDF) on 29 May 2004.
  100. PMID 2005573
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  101. PMID 16690809
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  102. ^
    PMID 22017262
    .
  103. PMID 30466474
    .
  104. ^
    PMID 22252602
    .
  105. ^
    PMID 15657340
    .
  106. ^
    PMID 18948763
    .
  107. PMID 18559852
    .
  108. ^
    PMID 21306759
    .
  109. S2CID 37705117
    .
  110. PMID 29879107
    .
  111. S2CID 54400632
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  112. ^ "Soft Tissue Sarcoma". National Cancer Institute. National Institutes of Health, U.S. Department of Health and Human Services. January 1980.
  113. PMID 22126291
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  114. PMID 19289832
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  115. PMID 22245111
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  116. PMID 24077454
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  117. doi:10.1101/2020.02.20.956557
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  118. OCLC 1113687835
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  119. S2CID 17931210
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  120. OSTI 133832
    .
  121. S2CID 38574543
    .
  122. S2CID 40303322
    .
  123. PMID 15758010
    .
  124. PMID 11773279
    .
  125. PMID 16495912
    .
  126. S2CID 18279123
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  127. ^
    PMID 20207580
    .
  128. PMID 20664922
    .
  129. PMID 27229488
    .
  130. PMID 18773966
    .
  131. S2CID 19854416
    .
  132. PMID 18841054
    .
  133. PMID 17219444
    .
  134. S2CID 42034181
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  135. S2CID 206871351
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  136. PMID 19230772
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  137. PMID 16960145
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  138. S2CID 19558322
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  139. S2CID 25070861
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  148. S2CID 9556660
    .
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