Methylation A Tool in Cancer Treatment – Expressing Silenced Tumour Suppressor Genes

A Tool in Cancer Treatment – Expressing Silenced Tumour Suppressor Genes

DNA Methylation and Epigenetics

DNA is like a script of the human body that tells each cell in your body which gene to express and which gene to silence. There are many different cells in the body that provide different functions such as, muscle cells, epithelial cells (stomach, intestinal cells), nerve cells, etc. Every cell in the human body contains the same DNA but yet there are many different cells in the human body that have different functions. This is because some genes are switched off and others are switched on! For example a muscle cell needs a higher number of mitochondria then other cells because a muscle cell requires much more energy than other cells. The DNA in the muscle cell will express cell specific genes and silence others; this is how you get cell differentiation.

DNA Methylation is one way in which a cell will express cell specific genes and silences others; if every cell in the body expressed the same genes there would be no cell differentiation. In a cell, if a gene is methylated then the gene cannot be expressed, in no way what so ever! Genes have ‘block DNA sequences’ in front of a gene, called promoters. A gene promoter will promote the expression of the gene. If the promoter is repressed or methylated then the gene will not be expressed in the cell!

• Gene promoters often have HIGH CG* dinucleotide content (CpGs). These “CpG” islands are located in a region in many gene promoters. CpG island Methylation controls cell-specific gene expression UNDER NORMAL CONDITIONS therefore CpG island Methylation is crucial in the control of gene expression.

*CG meaning
C = Cytosine Nucleotide
G = Guanine Nucleotide

FACT! About 50% of genes have 5’ CpG Islands!

Therefore gene expression can be regulated by addition of methyl groups (Methylation) to Cytosine bases! See Picture to the bottom right!

As I said earlier in the Hub, if a gene is methylated, gene expression will not occur! This is why gene expression can be regulated through adding a methyl group to the nucleotide cytosine.

• All cells contain Tumour suppressor genes. These genes will be activated if the cell detects anything abnormal such as, the gene that controls cell division is not working properly. The cell will not stop dividing if the gene that controls cell division is not working properly and a tumour will develop. Under normal conditions a cells tumour suppressor genes will be expressed, thus processes like apoptosis (cell death), DNA repair, etc would occur. The tumour suppressor genes will either destroy the cell so that the genes are not passed on as the cell tries to divide or attempt to repair the damaged DNA strand.
• As cells age random Methylation can occur. If Methylation happens in the promoter regions of Tumour suppressor genes then they become silenced! As the tumour suppressor gene is silenced the cells defences against tumours is non existent. It is believed that inactivation of genes is at least as common or more frequent than, mutational events in the development of cancer!

Demethylation and Switching The Gene Back on!

• Drugs have been developed that have a similar structure to Cytosine but are slightly different. Since the structure 5’Aza2’deoxycytidine (drug) is similar to cytosine the drug can integrate with the DNA and instead of CpG islands, the promoter region will now be ACpG islands. The ACpG islands cannot be Methylation as a methyl group can not bind to 5’Aza2’deoxycytidine. The tumour suppressor genes are therefore demethylated and the expression of the tumour suppressor genes are now SWITCHED ON! The cell will now go to work and suppressor the tumour as it would have done before.

Example!

• CpG Islands = CGCGCGCGCGCGCGC
• ACpG Islands = ^ACG^ACG^ACG^ACG^ACG

Methylation will not occur on ACpG islands but will occur on CpG islands.

Hundreds of genes have been found to inappropriately methylated in cancer including

• P53
• RB
• Cyclin Dependent kinase inhibitor (p16,14,15,18,19 etc)
• VHL
• APC (Adenomatous polyposis coli protein)
• BRCA1
• BRCA2
• CASP3 (Caspase 3 (Apoptosis))
• Cadherins
• MLH1 (mismatch repair gene)
• RADDF1-5
• SFRP1

Now scientists are trying to identify Epigenetically Silenced Tumour Suppressor Genes in Cancers. Drugs are being developed to administer to cancer patients whose genes have been methylated in order to demethylate the tumour suppressor genes (making the tumour suppressor gene active again).

This is another tool in the fight to defeat cancer. Demethylation of tumour suppressor genes is fairly new and still needs plenty of research although there have already been success stories!!

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Thanks

Mike