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

An example of a DNA molecule
An example of a DNA molecule

DNA Methylation and Epigenetics

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!


Showing how cytosine become methylated. As seen a Methyl group is added to cytosine.
Showing how cytosine become methylated. As seen a Methyl group is added to cytosine.
  • 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.


Example of Methylation  Click to make it bigger has I had to make this imagine small to fit on the Hub.
Example of Methylation Click to make it bigger has I had to make this imagine small to fit on the Hub.
  • 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!

Cytosine Structure in comparison to Azacitidine Structure
Cytosine Structure in comparison to Azacitidine Structure

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 = ACGACGACGACGACG

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!!

If you find my Hub interesting don't hesitate in leaving a comment, I would really appreciate it.


Thanks

Mike

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Comments 1 comment

Freddie 3 years ago

Many people do not rlaieze the prevelance of CP and it's very frustrating to parents like me that have a child with CP. Those stats you posted are very correct, however those numbers are only based off of 3 states, Wisonsin, Georgia, and another state I can't think of off the top of my head. Reaching for the Stars A Foundation of Hope for Children with Cerebral Palsy, was founded in 2004, to start a movement to try to attract more funding and more education for children with CP. I as a parent have written many legislators about CP, and usually I get a letting thanking me for my support about Cystic Fibrosis research, which really begs to ask the question.."do they really read our letters?" For the last 4 years or so RFTS has been to capital hill lobbying to get the $10 Million from the house of appropriations to give to the CDC to get a national surveillance and Epidemiology study for CP, which doesn't exist for CP currently. But it is ignored. RFTS is also the organization that stepped up and raised the money for the CDC to have the first ever prevelance study, which had NEVER been done before. Boy were they shocked when the previous estimate of 1 in 666, was really 1 in 278. Their logic of thinking is that this is where Autism Speaks started...they got the numbers to WOW the public, to reel them in...and it's just not happening. Even celebs with family members with CP, decline Ashton Kutchers twin brother has CP...he states they are astranged, so therefore wants nothing to do with it. Then we have Cheryl Hines, who has a nephew, a very close nephew with it...she has also declined to talk about his struggles. The NIH reports that CP recieved about $18 Million in funding, while Autism recieves more then $128 million. We have foundation like the UCP, who you'd think would give all their money to CP research, when in fact they give less then about 40% to CP research. The rest goes to other undiagnosed disorders or other neuromuscular disorders. In the last 50 years we have not come very far in our research...we still to this day can not figure out why 1 preemie gets CP, and another at the same gestational age and weight doesn't. And now that preemies are being saved at as little as 23 weeks gestation, the CP numbers are likely to keep going up, up and up....The time for research is now. The average liftime cost of a child with CP, will be about $1 Billion more then the average child, due to the numerous surgeries they have, medications, treatments for spasicity, Physical Therapy, Occupational Therapy. Most of that money will come from tax payers. When insurance companies refuse to cover kids with "pre-existing conditions" and when the life time max are hit, parents have no choice but to quit their jobs, to go on medicaid..true story, just had a friend that had to do that very thing..she made too much money working to get medicaid, no insurance company would touch her 1 year old with CP, so she was told BY MEDICAID to quit her job, so she could qualify...that's what she had to do. Going without seizure medication, spasicity treatments, and nutritional supplement is not an option. The government needs to look at that 1 in 278, and rlaieze that many of them will grow up turn 18 and immediately start to collect Social Security and medicaid, because the leg work wasn't done correctly as children to allow them to live an independent life. Thank you so much for blogging about this, and for bringing attention to a cause that deserves much much more.

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