DNA methylation in cancer

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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. [1]

Contents

All mammalian cells descended from a fertilized egg (a zygote) share a common DNA sequence (except for new mutations in some lineages). However, during development and formation of different tissues epigenetic factors change. The changes include histone modifications, CpG island methylations and chromatin reorganizations which can cause the stable silencing or activation of particular genes. [2] Once differentiated tissues are formed, CpG island methylation is generally stably inherited from one cell division to the next through the DNA methylation maintenance machinery. [2]

In cancer, a number of mutational changes are found in protein coding genes. Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations that silence protein expression in the genes affected. [3] However, transcriptional silencing may be more important than mutation in causing gene silencing in progression to cancer. [4] In colorectal cancers about 600 to 800 genes are transcriptionally silenced, compared to adjacent normal-appearing tissues, by CpG island methylation. Such CpG island methylation has also been described in glioblastoma [5] and mesothelioma. [6] Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs. [7]

CpG islands are frequent control elements

CpG islands are commonly 200 to 2000 base pairs long, have a C:G base pair content >50%, and have frequent 5' → 3' CpG sequences. About 70% of human promoters located near the transcription start site of a gene contain a CpG island. [8] [9]

Promoters located at a distance from the transcription start site of a gene also frequently contain CpG islands. The promoter of the DNA repair gene ERCC1 , for instance, was identified and located about 5,400 nucleotides upstream of its coding region. [10] CpG islands also occur frequently in promoters for functional noncoding RNAs such as microRNAs and Long non-coding RNAs (lncRNAs).

Methylation of CpG islands in promoters stably silences genes

Genes can be silenced by multiple methylation of CpG sites in the CpG islands of their promoters.[11] Even if silencing of a gene is initiated by another mechanism, this often is followed by methylation of CpG sites in the promoter CpG island to stabilize the silencing of the gene.[11] On the other hand, hypomethylation of CpG islands in promoters can result in gene over-expression.

Causes of DNA hypermethylation are: - Mediation of mutated K-ras induced jun protein (Serra RW. et al. 2014; Leppä S. et al. 1998) - the inhibitory effect of lnRNA on miRNAs causing demethylation - their "absorption" in the sponge effect or direct repression of demethylation factors TET1 and TGD (Thakur S. Brenner C. 2017; Ratti M. et al. 2020; Morita S. et al. 2013) - Activation of DNA methylases (Kwon JJ. et al. 2018) - Changes in isocitrate dehydrogenase (Christensen BC. et al. 2011) - Effects of viruses (Wang X. et al. )

 Causes of DNA hypomethylation: - The effect of mutated K-ras on long non-coding RNAs, which, when acting, a) directly inhibits the activity or translation of genes encoding DNA methylases (Sarkar D. et al. 2015) b) rather, "sponges" absorb miRNAs (Ratti M. et al. 2020 ), which should ensure the functioning of DNA methylases - The effect of mutated K-Ras through the activation of the myc-ODC axis, the mTor complex, with the consequence of the synthesis of polyamines, the activation of which, figuratively speaking, "pumps out" single-carbon fragments from the Methionine cycle and creates a lack of substrate for DNA methylation, leading to a hypomethylated state of DNA (Урба К. 1991 ) - Changes in the activity of methylases DNMT1/3A/3B, their relocalization (Hoffmann MJ, Schulz WA. 2005; Nishiyama A. et al. 2021) - Changes in TET performance (Nishiyama A. et al. 2021) - Changes in the synthesis of SAM from methionine due to changes in the enzymes MAT (Frau M. et al. 2013) - Changes in serine catabolism (Snell K., Weber G. 1986), causing more intensive removal of homocysteine from the methionine cycle, when serine binds to homocysteine (Урба К. 1991) - Other, unspecified reasons for supplying the Met cycle with single-carbon fragments, causing e.g. "methyl trap" phenomenon (Shane B. Stokstad EL. 1985; Zheng Y, Cantley LC. 2019), sietin and with disorders of vitamin B12 metabolism, disruption of the spare methionine resynthesis pathway (Ouyang Y. et al. 2020; Ozyerli-Goknar E, Bagci-Onder T. 2021; Barekatain, Yasaman et al. 2021) or other monocarbon fragment metabolism disorders (Urba K. 1991).

Promoter CpG hyper/hypo-methylation in cancer

In cancers, loss of expression of genes occurs about 10 times more frequently by hypermethylation of promoter CpG islands than by mutations. For instance, in colon tumors compared to adjacent normal-appearing colonic mucosa, about 600 to 800 heavily methylated CpG islands occur in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. [11] [12] [13] In contrast, as Vogelstein et al. [3] point out, in a colorectal cancer there are typically only about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.

DNA repair gene silencing in cancer

In sporadic cancers, a DNA repair deficiency is occasionally found to be due to a mutation in a DNA repair gene. However, much more frequently, reduced or absent expression of a DNA repair gene in cancer is due to methylation of its promoter. For example, of 113 colorectal cancers examined, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region. [14] Similarly, among 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, 6 had a mutation in the PMS2 gene, while for 103 PMS2 was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). [15] In the remaining 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1. [16]

Frequency of hypermethylation of DNA repair genes in cancer

Twenty-two DNA repair genes with hypermethylated promoters, and reduced or absent expression, were found to occur among 17 types of cancer, as listed in two review articles. [17] Promoter hypermethylation of MGMT occurs frequently in a number of cancers including 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers.[ citation needed ] That review also indicated promoter hypermethylation of LIG4 , NEIL1 , ATM , MLH1 or FANCB occurs at frequencies between 33% and 82% in one or more of head and neck cancers, non-small-cell lung cancers or non-small-cell lung cancer squamous cell carcinomas. The article Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer indicates the DNA repair gene WRN has a promoter that is frequently hypermethylated in a number of cancers, with hypermethylation occurring in 11% to 38% of colorectal, head and neck, stomach, prostate, breast, thyroid, non-Hodgkin lymphoma, chondrosarcoma and osteosarcoma cancers (see WRN).

Likely role of hypermethylation of DNA repair genes in cancer

As discussed by Jin and Roberston in their review, [17] silencing of a DNA repair gene by hypermethylation may be a very early step in progression to cancer. Such silencing is proposed to act similarly to a germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer. Another review [18] also indicated an early role for hypermethylation of DNA repair genes in cancer. If a gene necessary for DNA repair is hypermethylated, resulting in deficient DNA repair, DNA damages will accumulate. Increased DNA damage tends to cause increased errors during DNA synthesis, leading to mutations that can give rise to cancer.

If hypermethylation of a DNA repair gene is an early step in carcinogenesis, then it may also occur in the normal-appearing tissues surrounding the cancer from which the cancer arose (the field defect). See the table below.

Frequencies of hypermethylated promoters in DNA repair genes in sporadic cancers and in adjacent field defects
CancerGeneFrequency in CancerFrequency in Field DefectRef.
ColorectalMGMT55%54% [19]
ColorectalMSH213%5% [20]
ColorectalWRN29%13% [21]
Head and NeckMGMT54%38% [22]
Head and NeckMLH133%25% [23]
Non-small cell lung cancerATM69%59% [24]
Non-small cell lung cancerMLH169%72% [24]
StomachMGMT88%78% [25]
StomachMLH173%20% [26]
EsophagusMLH177%-100%23%-79% [27]

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. [28] [29] [30] [31] The DNA damages that accumulate due to hypermethylation of the promoters of DNA repair genes 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. [32] 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 island 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 promoter methylation alterations in tumors. Some of these alterations may contribute to cancer progression.

DNA methylation of microRNAs in cancer

In mammals, microRNAs (miRNAs) regulate the transcriptional activity of about 60% of protein-encoding genes. [33] Individual miRNAs can each target, and repress transcription of, on average, roughly 200 messenger RNAs of protein coding genes. [34] The promoters of about one third of the 167 miRNAs evaluated by Vrba et al. [35] in normal breast tissues were differentially hyper/hypo-methylated in breast cancers. A more recent study pointed out that the 167 miRNAs evaluated by Vrba et al. were only 10% of the miRNAs found expressed in breast tissues. [36] This later study found that 58% of the miRNAs in breast tissue had differentially methylated regions in their promoters in breast cancers, including 278 hypermethylated miRNAs and 802 hypomethylated miRNAs.

One miRNA that is over-expressed about 100-fold in breast cancers is miR-182. [37] MiR-182 targets the BRCA1 messenger RNA and may be a major cause of reduced BRCA1 protein expression in many breast cancers [38] (also see BRCA1).

microRNAs that control DNA methyltransferase genes in cancer

Some miRNAs target the messenger RNAs for DNA methyltransferase genes DNMT1, DNMT3A and DNMT3B, whose gene products are needed for initiating and stabilizing promoter methylations. As summarized in three reviews, [39] [40] [41] miRNAs miR-29a, miR-29b and miR-29c target DNMT3A and DNMT3B; miR-148a and miR-148b target DNMT3B; and miR-152 and miR-301 target DNMT1. In addition, miR-34b targets DNMT1 and the promoter of miR-34b itself is hypermethylated and under-expressed in the majority of prostate cancers. [42] When expression of these microRNAs is altered, they may also be a source of the hyper/hypo-methylation of the promoters of protein-coding genes in cancers.

Related Research Articles

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

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.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

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.

<span class="mw-page-title-main">DNA methylation</span> Biological process

DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis.

<span class="mw-page-title-main">Neoplasm</span> Tumor or other abnormal growth of tissue

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, which may be called a tumour or tumor.

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.

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

<span class="mw-page-title-main">DNA mismatch repair</span> System for fixing base errors of DNA replication

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

<span class="mw-page-title-main">Base excision repair</span> DNA repair process

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

<span class="mw-page-title-main">MSH2</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.

<span class="mw-page-title-main">MLH1</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

<span class="mw-page-title-main">MSH6</span> Protein-coding gene in the species Homo sapiens

MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6. The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair.

<span class="mw-page-title-main">Methylated-DNA-protein-cysteine methyltransferase</span> Mammalian protein found in Homo sapiens

Methylated-DNA--protein-cysteine methyltransferase(MGMT), also known as O6-alkylguanine DNA alkyltransferaseAGT, is a protein that in humans is encoded by the MGMT gene. MGMT is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.

<span class="mw-page-title-main">MBD4</span> Protein-coding gene in the species Homo sapiens

Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.

Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthetic lethality to mean the situation arising by virtue of a combination of deficiencies of two or more genes leading to cell death, whereas a deficiency of only one of these genes does not. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not result in cell death, although the effect of that mutation could result in a differing phenotype, and then systematically test other mutations at additional loci to determine which, in combination with the first mutation, causes cell death arising by way of deficiency or abolition of expression.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

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.

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.

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.

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.

References

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Ruben Agrelo,* Wen-Hsing Cheng,† Fernando Setien,* Santiago Ropero,* Jesus Espada,* Mario F. Fraga,* Michel Herranz,* Maria F. Paz,* Montserrat Sanchez-Cespedes,* Maria Jesus Artiga,* David Guerrero,‡ Antoni Castells,§ Cayetano von Kobbe,* Vilhelm A. Bohr,† and Manel Esteller*¶Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer.Proc Natl Acad Sci U S A. 2006; 103(23): 8822–8827.

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