Melanoma is a rare but aggressive malignant cancer that originates from melanocytes. These melanocytes are cells found in the basal layer of the epidermis that produce melanin under the control of melanocyte-stimulating hormone. Despite the fact that melanoma represents only a small number of all skin cancers, it is the cause of more than 50% of cancer-related deaths. The high metastatic qualities and death rate, and also its prevalence among people of younger ages have caused melanoma to become a highly researched malignant cancer. Epigenetic modifications are suspected to influence the emergence of many types of cancer-related diseases, and are also suspected to have a role in the development of melanoma.
In the last few years, chemical alterations in the genome have become more evident, and these alterations can be critical in the development of malignancy. This alteration process is referred to as epigenetics (Patino et al. 2008). Epigenetics is the term used to refer to stable changes in DNA that affect gene expression but do not involve changes in the underlying nucleotide sequence of the organism (Patino et al. 2008). The mechanisms by which epigenetics occur involve hypo- and hypermethylation of DNA, histone modifications by acetylation, methylation, and phosphorylation, and posttranslational modifications which include RNA silencing. These modifications can cause different expression patterns to occur, which can result in alterations to cells. Some of these alterations could result in the formation of cancerous cells or various other dangerous changes in cell function, among many other outcomes when paired together. Cancerous cells are not formed from just one change.
Role of cytosine methylation in melanoma
In epigenetic alterations in cancer, DNA methylation is the most studied, although it is not the only alteration that can occur. DNA methylation is a covalent modification of DNA where a methyl group is added to the C-5 position of cytosine by DNA-methyltransferases. This occurs mostly at the cytosine-phosphate-guanine dinucleotide rich regions, known as CpG islands, and are located particularly in the promoter regions of genes in the human genome (Patino et al. 2008). These promoter regions are methylated in certain ways or can be completely unmethylated. However, in an altered methylation of the CpG islands (generally where the methylation pattern is inverted), transcription can be altered which can lead to cancer. This is due to chromosomes being highly condensed, preventing RNA polymerase and other transcription factors from recognizing and binding to the DNA. This can result in gene silencing. This silencing of genes can be dangerous to cells, especially when the genes silenced are active in maintaining the cell cycle. The table below shows some of the important genes targeted by promoter hypermethylation in melanoma.
TABLE 1. Various genes targeted by promoter hypermethylation in malignant melanoma
Gene
Frequency of alteration within Melanoma (%)
RASSF1A
36- 57
APC
19
PYCARD
50
RARB
20- 70
MGMT
0- 34
DAPK
19
3- OST- 2
56
CDKN1B
0- 9
INK4A
10- 20
HOXB13
20- 33
SYK
30- 89
PRDX2
8
PTEN
0- 62
Some of the genes affected by cytosine methylation in melanoma formation
INK4A
INK4A, also known as p16, is a tumor suppressor gene and is found to have hypermethylated promoter regions in 10- 20% of melanoma cells and is involved in 40- 87% of gene alterations in melanoma cases (Gonzalgo et al., 1997). This means that 10- 20% of the time there is an epigenetic change in the INK4A gene, and 40- 87% of the time there is a nucleotide mutation in the gene. INK4A is one of the genes that is both epigenetically and genomically altered. As a regularly functioning gene, INK4A is a tumor suppressor that functions to repress the formation of tumors. The hypermethylation of this gene can cause it to become inactivated (Straume et al., 2002). When INK4 is inactivated through hypermethylation, it causes an interruption of the CDK4 and CDK6 genes, which normally stop cell growth in the G1 phase of cell division. When this happens, there is no regulation in the cell and it grows quickly and becomes cancerous.
SYK
SYK is another gene that is affected by cytosine methylation during cancer progression. It is a gene that, when hypermethylated, loses function (Muthusamy et al., 2006). This gene is found in 30- 89% of melanoma cases (Dahl et al., 2007), and causes cells to grow quickly. This fast growth is important in the quick metastasis of melanoma cells, and when hypermethylated, the growth and spread of cells slow considerably (Hoeller et al., 2005). This is a controversial finding with inconclusive results, though. Some findings show that normally functioning SYK genes aids in tumor suppression, while other studies find that it is a transforming factor that facilitates cancer formation. Normally functioning, the SYK gene produces a non- receptor protein kinase enzyme that aids in differentiation, proliferation, and phagocytosis among many other important processes. SYK is found expressed in a variety of cells including fibroblasts, epithelial cells (where it controls cell division and acts as a tumor suppressor), hepatocytes, and neuronal cells (TORCIS Bioscience, 2014). Although SYK does not have any reported DNA modifications, the epigenetic changes still cause sufficient damage to cells. When SYK silencing is coupled with other alterations, both genetically and epigenetically, cancer can form.
Role of histone modification in melanoma
Histone modifications play a large role in epigenetics because of their widely varied methods of occurrence and affect. Modifications to histones come about in many forms, with many still not being clearly understood. Methylation, acetylation, phosphorylation, and ubiquitination are the main categories of histone modification, with combinations of changes resulting in a range of genetic expression.
Histone methylation generally causes genes to turn off. Methylation of histones is also important for maintaining heterochromatin boundaries and a misregulation can lead to over expression or under expression of genes. This over expression or under expression can lead to the formation of cancer cells within an organism. On the other end of the spectrum, demethylation causes genes to turn on. This activation can be just as detrimental to cells, as their processes are disrupted by unnecessary gene products. Most histone methylation occurs in the promoter region, and is similar to cytosine methylation in process and function.[1]
Histone acetylation is generally associated with transcription activation, which can cause certain proteins to be coded for and expressed when they shouldn't be. This can potentially lead to cancer. Conversely, deacetylation of genes causes transcription to be inhibited, shutting down important biological processes within the cell. In melanoma, Ku70 and Ku86 genes involved in DNA repair, were found to be inactivated when a histone deacetylase, or HDAC, was exposed to the gene (Munshi et al., 2005).
Histone phosphorylation is the process by which a phosphate group is added to histone tails. This process drastically changes histone structure and shape. It has been discovered that phosphorylation causes post translational changes, with binding domains having been found, in addition to regulations in DNA repair, transcription regulation, and chromatin condensation. One of the major phosphorylations in DNA repair is the H2AX location. When H2AX is phosphorylated, it spreads throughout the DNA break and is thought to recruit acetyltransferases to relax the DNA and allow repair proteins to access the damaged portion (Rossetto et al., 2012). Phosphorylation of histones begins the process of DNA repair, and it is important for signaling other processes to begin, including cell division . H2AX is an indicator of melanoma because of its high correlation to chromosomal instability (Warters et al., 2005). When high levels of H2AX are present, more phosphorylation occurs and chromosomes are more susceptible to damage. Histone phosphorylation of H3S10 has been shown to associate with H3 acetylation, which is integral in transcription activation (Rossetto et al., 2012). If transcription is altered, cells are generally negatively impacted and they react in adverse ways that may harm the organism.
Roles microRNAs play in melanoma development
Scientists have wondered how melanoma cells travel from major tumors found on the surface of the skin to the liver, brain, lungs and other organs where they become very destructive, resistant to treatments and even cause death. Research being conducted tries to answer the question of how and why melanoma cells become defective and cause harm to people. Many studies have found that some classes of short strands of RNA, called microRNAs, are linked to these harmful properties of melanoma cells.
MicroRNAs (miRNAs) are non-coding RNAs of roughly 20-22 nucleotides in length. They function in post-transcriptional gene regulation, preventing a particular protein from being produced. They can do this in many ways, such as binding to and destroying the messenger RNA that otherwise would have produced the protein. MiRNAs have also been shown to bind directly to messenger RNA and silence them before they are able to be translated into proteins which would play important roles in transcription (O'Donnell et al., 2005). There are roughly 1000 miRNAs in the human genome, and about 33% of all human messenger RNAs are under their control (Liu et al. 2012).
MiRNAs function in several areas of biological processes, including differentiation, proliferation and apoptosis. They have also been found to play important roles in the development of cancers. Some of these non-coding RNAs, including miRNA-205, have been linked, recently, to the over or under expression of several genes associated with cancer and other life-threatening diseases such as heart disease, and alterations in their expressions have been shown to impact cancer cell growth, survival and the ability to spread (Liu et al. 2012). For instance, the loss of the miRNA-205 expression is associated with the metastasis of melanoma (Liu et al. 2012). An overproduction of MiRNAs can cause the epigenetic silencing of many important genes such as MITF, FOXO3, TFAP2C, CCND1, ITGA3 and c-KIT, needed in cell cycle regulation, and this can cause a cell to become cancerous (He et al., 2005).
MicroRNAs and genes involved in melanoma
A particular miRNA, MiR-182, has been found to impact MITF and FOXO3, which are tumor suppressor genes. MiR-182 is a member of a miRNA cluster in a chromosomal locus that is most often amplified in melanoma (Segura et al. 2009). It is frequently up-regulated in human melanoma tissue samples and cell lines, and this up-regulation causes its ectopic expression, which stimulates migration of melanoma cells, both in vitro and in vivo. The down-regulation of this miRNA triggers apoptosis. Over-expression of miR-182 in malignancy has been shown to negatively impact these tumor suppressor genes by directly repressing them. The repression of these genes allows miRNA to promote the spread and migration of melanoma cells, not taking into account the properties necessary for metastasis to occur.
In a fairly recent experiment done by Penna et al. on miRNA-214, it was shown that the miRNA regulates the expression of a panel of 11 target genes, including TFAP2C and ITGA3, and contributes to melanoma tumor progression by suppressing those genes. In this experiment, these genes, known to contain one or more binding sites of the miRNA, were obtained and their three prime untranslated regions (3'UTRs) cloned into a vector. Luciferase assays were then performed in MA-2 and/or MC-1 cells transfected with the miRNA. It was reported that luciferase expression, which was driven by the 3'UTRs of integrin alpha 3 (ITGA3) or transcription factor AP-2 gamma (TFAP2C), was repressed significantly. The team then tried to assess whether the luciferase expression regulation seen in the ITGA3 and TFAP2C genes depended on the binding between the miRNA and the complementary sequence that was present on the 3'UTRs of either gene. A four nucleotide deletion or three point mutations were respectively inserted in the ITGA3 or TFAP2C 3'UTRs, and the 3'UTR alterations entirely abrogated the effect of the miRNA over-expression on luciferase expression in the MA-2 and MC-1 cells. This observation indicated the direct regulation of miRNA-214 on the 3'UTR binding sites of the ITGA3 and TFAP2C genes.
Further experiment on protein expression was also conducted on these two particular genes, TFAP2C and ITGA3, and it was shown that miRNA-214 over-expression led to a 30-90% protein decrease in ITGA3 and a 40-80% decrease in TFAP2C (Penna et al., 2011). Consistently, proteins were upregulated 20% in the ITGA3 and 40% in the TFAP2C when miRNA-214 was silenced in the MC-1 cell. This suggests that miRNA-214 importantly regulates the expression of the ITGA3 and TFAP2C genes and promotes melanoma tumor progression when overly expressed.
TABLE 2. Various genes altered by general mutations or amplification in malignant melanoma
Gene type
Gene Name
Alteration Type
Frequency of alteration within Melanoma (%)
Proto- oncogenes
NRAS
Mutation
15- 25
BRAF
Mutation
50- 70
KIT
Mutation
2- 10
CDK4
Mutation, amplification
0- 9
CTNNB1
Mutation
2- 23
MITF
Amplification
10- 16
CCND1
Amplification
6- 44
PIK3CA
Mutation
<5
AKT3
Amplification
40- 60
Tumor Suppressor Genes
INK4A
Mutation
40- 87
ARF
Mutation
40- 70
PTEN
Mutation
5- 40
TP53
Mutation
0- 25
Many genes are altered genetically and epigenetically in cancers, which is one of the reasons cancer is so hard to combat. INK4A and PTEN are two genes that are in both Tables 1 and 2 above, as they are both epigenetically and genetically mutated in melanoma cases. This is not uncommon, as cells need multiple changes to the genome to initiate a change as large as cancer. The epigenetic side of cancer research is growing and uncovering many overlaps like in the cases of INK4A and PTEN, giving a larger, more accurate image of cancer and melanoma. The complexity and variability of cancer epigenetics makes this a growing and important field. Since epigenetic modifications are able to be reversed, this makes them a target for therapeutics and part of the future of cancer combat, and specifically melanoma, due to its deadliness and difficulty to catch. The genes listed above are only the beginning of a long list of available treatment areas that could potentially reverse or prevent melanoma if detected early.
Related Research Articles
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.
In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.
An epigenome consists of a record of the chemical changes to the DNA and histone proteins of an organism; these changes can be passed down to an organism's offspring via transgenerational stranded epigenetic inheritance. Changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome.
Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.
Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.
In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.
Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.
Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.
Epigenetic therapy refers to the use of drugs or other interventions to modify gene expression patterns, potentially treating diseases by targeting epigenetic mechanisms such as DNA methylation and histone modifications.
Epigenetics of physical exercise is the study of epigenetic modifications to the cell genome resulting from physical exercise. Environmental factors, including physical exercise, have been shown to have a beneficial influence on epigenetic modifications. Generally, it has been shown that acute and long-term exercise has a significant effect on DNA methylation, an important aspect of epigenetic modifications.
Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation. DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.
DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.
CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.
Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.
Epigenetics of autoimmune disorders is the role that epigenetics play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.
Epigenetics of chronic pain is the study of how epigenetic modifications of genes affect the development and maintenance of chronic pain. Chromatin modifications have been found to affect neural function, such as synaptic plasticity and memory formation, which are important mechanisms of chronic pain. In 2019, 20% of adults dealt with chronic pain. Epigenetics can provide a new perspective on the biological mechanisms and potential treatments of chronic pain.
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