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DNA methylation is an epigenetic mechanism plays a pivotal role in gene expression. Cancer is one of the complex diseases caused by mutations in genes that play a role in cell cycle arrest; cell proliferation; cell growth; etc apart from this epigenetics modifications in genes also leads to cancer. Proto oncogene is converted to oncogene when the promoter region is hypomethylated; in this case the gene is always transcribed. In tumour suppressor gene the promoter region is hypermethylated to silence its function. These two factors promote tumour growth. Somatostatin (SST) a tumour suppressor gene is hypermethylated in the promoter region of the gene and cause Gastric Adenocarcinoma. A genome wide analysis showed the silencing of SST by epigenetics mechanism in Colon Cancer. In this review, I discussed the SST gene silencing by epigenetics mechanism in Gastric Adenocarcinoma and Colon Cancer.
The mechanism of silencing or activation of gene expression without making any mutations or recombination or translocation or changes in DNA sequence of the gene was termed as Epigenetics. The important molecular stages are also mediated by epigenetics mechanisms there are, expression of a gene by DNA methylation, chromatin remodeling by acetylation, phosphorylation, methylation of N-terminal end of histone tails, binding to polycomb proteins. By the role of these described epigenetics mechanisms the 3D organization of nucleus is maintained.
DNA methylation is one of the epigenetics mechanism is often dysregulated by tumour cells to make tumour cells survive, proliferation to attain malignancy. This DNA methylation changes is used as a early biomarker in tumour, to follow tumour progression, and tumour prognosis. The high efficiency therapeutic treatments are available, target against deregulated DNA methylation process. In case of primary tumour (early stage of tumour) the treatment against deregulated DNA methylation will rescue the normal gene function and by that the tumour promoting pathway will be blocked.
Gastric Cancer is found mostly in western countries. Improper diet, excess fat intake, physical inactivity, obesity leads to gastric cancer. In recent studies showed the epigenetics silencing of SST tumour suppressor gene is found in human Gastric Cancer sample and Colon Cancer sample.
DNA METHYLATION MECHANISM:
The DNA sequence consists of promoter region and coding region. In promoter region the high repeats of CG (Cytosine Guanine) is present which is inversely proportional to coding region. This high repeats of CG is called as CpG Islands. The methylation of DNA is usually occurred in the Cytosine nucleotide of the CpG Island. DNMT3A and DNMT3B (DNA methyl transferase) are the enzymes which transfers a methyl group to cytosine.
Chromosome consists of telomere, euchromatin, heterochromatin, and centromere. The non coding region is otherwise called as heterochromatin which is transcriptional silenced by DNA hypermethylation.
DNA METHYLATION AND CANCER:
Cancer is one of the complex diseases and risk of death is high when it metastasis. In cancer proto oncogene is mutated in to oncogene and tumour suppressor gene is mutated and its function is deregulated. The mutation in tumour suppressor gene is recessive, so both alleles must be mutated to disrupt its full function.
In general the promoter region of a DNA sequence is always hypomethylated in order to express the gene in vice versa the gene is silenced if coding region of a DNA sequence is hypermethylated Fig 1. In some tumor cases the oncogene is always hypomethylated and that gene is expressed all the time. DNA hypermethylation of tumor suppressor gene results the silence of that particular gene. In such case some of the important mechanisms like DNA repair, apoptosis controlled by tumor suppressor gene will be blocked. This helps to transform primary tumor in to malignant stage.
Tumour suppressor genes somatostatin (SST), RB, APC, BRCA1 is hypermethylated in gastric cancer, Retinoblastoma, colon cancer, Breast Cancer.
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Fig 1: The figure 1 shows the promoter methylation pattern in CpG Island. Each rectangle box represents exons and line between boxes represents introns. (A) The CpG Island is found in promoter region of the gene usually unmethylated to express its function (arrow). (B) In case of cancer the CpG island present in the promoter region is hypermethylated in tumour suppressor gene to silence its function (X).
Somatostatin (SST) is a gene present in long arm of human chromosome 3 transcribed in to SST peptide (regulatory peptide). SST receptors are classified into SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5. The gene corresponding to each receptor is different and it is present in various chromosomes. SST induces cell cycle arrest, tumour suppressor protein p53, p21 via binding to five different receptors. SST is produced by various parts of the body depending on its necessity.
SST act as a growth hormone inhibitory factor by inhibit the secretion of gastric acid because of this, the motor activity of exocrine and endocrine production in gastrointestinal tract is regulated. Several mouse model studies and in vitro studies showed SST suppressed the tumour growth. So they suggested SST functions were like a tumour suppressor gene in human cancers.
SST blocks tumour growth by binding to its corresponding receptor. The binding of SST to SST receptor 1, 2, 4, 5 induce cell cycle arrest and it activates other tumour suppressor protein pRB and p21. SST receptor 3 directly stimulates apoptosis and it activates p53 and BAX. In general SST inhibits tumour growth via the following mechanisms regulating the release of mitogenic hormones, growth factors, activating the immune system, apoptosis, and other tumour suppressor genes.
In gastric cancer and colon cancer SST gene was silenced by aberrant methylation in the promoter region of the SST gene and promotes tumour growth.
SILENCING OF SST BY DNA METHYLATION IN GASTRIC CANCER:
SST is one of the tumour suppressor genes. It has a capability to regulate gastrointestinal tract through its unique mechanism. So SST gene malfunction will leads to Gastric Cancer.
In recent studies showed the SST gene silencing in gastric carcinoma samples. The SST mRNA expression was measured in primary gastric carcinoma samples and compared with normal gastric samples. The result showed the mRNA expression of SST is frequently low in Gastric cancer sample compared to normal sample.
The SST promoter region of -83 to +678bp from transcription start site was measured for DNA methylation levels in gastric cancer samples and normal samples. The methylation level in tumour sample is high when compared to normal samples. Same results were obtained when they perform the same experiments in gastric cancer cell lines.
REACTIVATION OF SST EXPRESSION IN GASTRIC CANCER CELLS:
The low SST mRNA expression of AGS gastric cancer cell line was treated with 5-aza-dC (In vitro treatment) showed reduction in methylation level from 95 to 76%. The combined treatment of 5-aza-dC with Trichostatin A (TSA) a histone deacetylase inhibitor showed much more reduction level of DNA methylation in AGS gastric cancer cell line. These reports confirmed the DNA hypermethylation is the reason for silencing of SST in gastric cancer.
SILENCING OF SST BY DNA METHYLATION IN COLON CANCER:
A genome wide analysis of SST gene silencing in colon cancer showed similar results. The mRNA expression level of SST gene is measured in primary colon cancer samples and compared with normal samples. The result confirms the low mRNA expression in colon cancer samples. The methylation level in promoter region of SST gene was measured in normal and colon cancer samples. The normal samples showed frequent methylation in promoter region however it is low when compared to methylation level in colon cancer samples. There is no association between the methylation levels of SST gene with age, gender, tumour site.
To further conform this strongly the colon cancer cell line with significant low SST mRNA expression levels was treated with 5-aza-dC a DNA methylase inhibitor. The result showed considerable up-regulation of SST mRNA expression. These two studies confirmed the epigenetics mechanism plays a role in silencing of SST gene in gastric and colon cancer.
Epigenetics plays a major role in expression of gene. In cancer, tumour suppressor gene is silenced due to DNA hypermethylation in the promoter region. This paves a way to tumour to attain malignant stage.
Somatostatin, a growth hormone inhibitory gene is silenced in gastric cancer and colon cancer. Several studies reported somatostatin as a tumour suppressor gene and its blocks tumour growth through its mechanisms. The DNA hypermethylation was found in the CpG island present in the promoter region of SST gene. This epigenetic mechanism leads to down regulation of SST gene and finally its tumour suppressor role is silenced in Gastric cancer and Colon Cancer.
The combination treatment with 5-aza-dC, inhibitor of DNA Methylase and Trichostatin A (TSA), inhibitor of histone deacetylase (HDAC) in Gastric cancer cell line, and 5-aza-dC treatment alone in colon cancer cell line can reactivate the epigenetically silenced Somatostatin gene.
The biological importance of DNA methylation in the regulation of Somatostatin gene expression and its role in Gastric and colon cancer is highly recognized. Through these reports we can use SST gene as biomarker which could be used for early diagnosis of gastric carcinoma and in colon cancer. Further animal model studies are needed to show the biological outcome of gastric cancer when the SST gene is silenced.