DNA Methylation in Cancer edit
DNA methylation functions as a regulator of gene transcription and has demonstrated that genes with abnormal levels of 5-methylcytosine in the promoter region cause gene regulation. [1] [2] DNA methylation is one of many epigenetic modifications responsible for uncontrolled abnormal cell growth, referred to as cancer. [3] DNA methylation is an essential process during embryonic development. In later somatic cells, patterns of DNA methylation are usually inherited to daughter cells.This modification has been linked through various studies correlating the abnormal DNA methylation levels which alters gene regulation, resulting in cancer.[3]
Epigenetic factors are not inherited through normal Mendelian genetics. The DNA alterations are reversible and research supports the mechanisms remain after cell division .[1] The link between DNA methylation and cancer has been established, but the exact cause for cancer in every case remains unknown. The DNA methylation mechanism occurs at a certain frequency in healthy individuals. [4] When a gene associated with cancer has an abnormal amount of methylation, the gene expression is regulated in a manner which causes cancer metastasis. [3] [1] [2] Aberrant DNA methylation patterns, hypermethylation and hypomethylation, compared to normal tissue have been associated with a large number of human malignancies. In numerous types of cancer, many individual or set of genes, which have been linked with a cancer form.[2] The relationship between the DNA methylation and tumor formation and progression operate on the two different levels, hypermethlyation and hypomethylation, which occur in particular patterns for different cancer forms.
Location edit
DNA methylation occurs sporadically throughout the human genome. [2] [1] [3][4] [6] [7]. No distinctive methylation target location with a clear role for gene expression in eukaryotic organisms has been identfied. A diagnostic genome for each cancer type would allow for better diagnosis and detection, but the scientific research is still needed to accomplish this goal.
Special attention has been placed on the DNA methylation patterns in CpG islands and promoter regions of a gene[2][7] [8] DNA methylation occurs at the fifth carbon position of the cytosine nucleotide in a DNA sequence. [2] [1] [6] [4] A CpG dinucleotide is a nucleotide sequence when a cytosine is followed by a guanine base in DNA strand. [2] [6] [4] While the probability for the CpG sequence should occur in equal frequency of 6%, the dinulceotide is only rarely observed, as 1% of all dinucleotides DNA sequences. [6] The CpG nucleotide location further supports hypermethylation interference with eukaryotic gene expression because of base pairing. The methylated cytosine base is followed by a guanine which is hydrogen bonded to a complementary cytosine base pair also methylated. This CpG structure creates two methyl groups sitting diagonally from one another in the middle of two DNA strands [6] The promoter region for the cell serves the purpose of the binding site for most transcription factors, which is the site for various gene regulation.[1] [2]
Mechanism edit
Two classes of DNA methyltransferase enzymes play a role in DNA methylation mechanism. [2] [3] [4] [6] The de novo methyltransferase are responsible for initial methylation in a DNA sequence and maintenance methyltransferase copy DNA sequence methylations during further DNA replication. [1] [3] The de novo methyl enzymes prevent transcription factors from binding to the CpG dinulceotide, including AP-2, c-Myc/Myn, the cyclic AMP-dependent activator CREB, E2F, and NFkB. [3]
Hypermethylation edit
Hypermethylation is when too many methyl groups are on a DNA strand, which does not allow for proper gene transcription.[1] Hypermethylation operates as a gene regulation method that prevents the transcription of chromosomes with tumor suppressor genes. [1] [2] During hypermethlyation, gene expression is turned off. A tumor suppressor gene is silenced in the human genome the corresponding protein does not formed. [2] The result is the proliferation of damaged cells within the human body, which under normal circumstances would be deactived by the tumor suppressor proteins. [2] The continued formation of damages cells in the body leads to cancer tumors.
Research indicates hypermethylation of tumor suppressor genes leads to gene inactivation and a selective cell growth model advantageous to the progression of cancerous cells. [2] [1] [4] This was observed in retinoblastoma by transient transfection experimentation.[4]
Hypomethylation edit
Hypomethylation promotes proto-oncogenes on chromosome and turns on gene expression.[1] [6] [4] Hypomethylation relates to initial cancer cell formation, but also cancer progression to more advanced stages. [6] The disease acceleration was observed by an decrease in the methylation levels of malignant tumors that were half the methyl concentration of benign tumors. [2] The malignant tumors showed more hypomethylation in the cells.
When hypomethylation occurs on a chromosome which codes for a proto-ocogene, the protein formed promotes cancerous cells. [2] [1] [6] [4] The lack of methyl groups allows for more gene transcription, which causes a surplus of protein expression. Hypomethylation causes the production of uncontrolled damaged cell growth. [6] This mechanism of methylation favors the oncogenesis process found in cancer patients. It has been shown the manipulation of hypomethylation can result in anticancer affects as a short term solution.[6] However, this practice could also results in the advanced progression of already damaged cells undergoing chemotherapy treatment. [6] Global hypomethylation has connected in the development and progression of cancer through different mechanisms.[11]
Link to Diet edit
Proper DNA replication depends on the certain reactants for methylation to be in the patient's regular diet. Methyl groups are derived from the human diet through folic acid, Vitamin B12, methionine, betaine and choline. [2] Hypomethylation has been observed in patient with minimal intake of the listed sources of methyl sources. [2] Cancer patients can accelerate the disease progression rate with a diet deficient in methyl sources.[2]
Methodology edit
Because the DNA modifications are still being researched the methodology for identifying cancerous methylation patterns greatly varies. Tumor-specific abnormal methylation patterns can be used for human therapeutics, detection, diagnosis, and eventually prevention once established.[2] [6] Detection techniques for DMRs are sodium bisulfite assay, cDNA microarray, restriction genome mapping, and CpG island microarrays.[2] [6] [7] [8]The sodium bisulfite assay is advantageous because it converts the cytosine to uracil bases in the unmethylated form, while ignoring methylated cytosines.[2] The assay yields a chromosome map, which highlights hypermethylated and hypomethylated DMTs locations on a gene.[2] Another application used for DNA methylation analysis is methylation-specific polymerase chain reaction.[2] [7] [8] The technique allows cells to reproduce the aberrant DNA methylation patterns and the scientist can observed if the abnormal patterns are inherited in subseqentent generations.[2] The patterns for DNA methylation can be compared in units of DMRs, usually a length of 1000 DNA base pairs.[3] DMRs can be measured by various microarrays and gel electrophoresis or absorbance titrations.[3] [6] From these techniques a genomic map for each type of cancer can be developed by similarities observed across of a large number of cancer patients.[7] [8]
Therapeutic Drugs edit
Because epigenetic factor can be reversed to original state, human therapeutics can target the mechanism for cancer treatment. Studies with demethylating drugs have shown cells can revert the gene silencing from hypermethylation. The drug would allow the tumor suppressor proteins to become actively expressed again. [2] DNMT inhibitor drugs are cytosine analogs, such as Vidaza™, Dacogen™, DHAC, kymarabine, and zebularine.[2] The designer drugs prevent the hypermethylation mechanism and cancer progression.[2] The five drugs are variations of cytosine, which contain a certain modification at the fifth position carbon in the pyrimidine ring.[2] These drugs are still in the clinical trial phase.
References edit
- ^ a b c d e f g h i j k l Das, Partha M.; Singal, Rakesh (NaN undefined NaN). "DNA Methylation and Cancer". Journal of Clinical Oncology. 22 (22): 4632–4642. doi:10.1200/JCO.2004.07.151. PMID 15542813.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help) - ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Lewandowska, J.; Bartoszek, A. (NaN undefined NaN). "DNA methylation in cancer development, diagnosis and therapy--multiple opportunities for genotoxic agents to act as methylome disruptors or remediators". Mutagenesis. 26 (4): 475–487. doi:10.1093/mutage/ger019. PMID 21551264.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help) - ^ a b c d e f g h i Bagga, Savita. "Introduction to DNA Methlylation". Sigma-Aldrich. Retrieved 14 March 2013.
- ^ a b c d e f g h i Phillips, Theresa. "The Role of DNA Methylation in Cancer". Scitable by Nature Education. Retrieved 15 March 2013.
- ^ "Diagram Damage to Cancer-Wiki". Retrieved 2 April.
{{cite web}}: Check date values in:|accessdate=(help) - ^ a b c d e f g h i j k l m n o Laird, P. W.; Jaenisch, R. (1994). "DNA methylation and cancer". Human Molecular Genetics. 3 Spec No: 1487–95. doi:10.1093/hmg/3.suppl_1.1487. PMID 7849743.
{{cite journal}}: Check date values in:|year=/|date=mismatch (help) - ^ a b c d e Saxena, A.; Dhillon, V. S.; Shahid, M.; Khalil, H. S.; Rani, M.; Prasad DAS T; Hedau, S.; Hussain, A.; Naqvi, R. A.; Deo, S. V.; Shukla, N. K.; DAS BC; Husain, S. A. (2012 Dec). "GSTP1 methylation and polymorphism increase the risk of breast cancer and the effects of diet and lifestyle in breast cancer patients". Experimental and Therapeutic Medicine. 4 (6): 1097–1103. doi:10.3892/etm.2012.710. PMC 3494109. PMID 23226781.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: date and year (link) - ^ a b c d e "Cancer Genetics". Annenberg Learner. Retrieved 1 April 2013.
- ^ "Genetics of Colorectal Cancer". National Cancer Institute. Retrieved 1 April 2013.
- ^ "Childhood Cancer- Genetics and Biology". Cancer Research UK. Retrieved 1 April 2013.
- ^ Epigenetics : a reference manual. Norfolk: Caister Acad. Press. ISBN 978-1-904455-88-2..
{{cite book}}:|first=has generic name (help);|first=missing|last=(help); Check|isbn=value: invalid character (help) - ^ "Study Flow Diagram". Retrieved 2 April 2013.
