In this video, we'll talk about carcinogenesis of colon cancer,

and we'll look it at a molecular level,

and see what kind of mutations occur along the DNA

that will result in cancer of the colon.

So, we begin by looking at normal colon cells that have their blood supply.

Here where the crypts are,

stem cells will migrate up, giving rise to new colon cells.

If we look into the genetic material of one of the stem cells,

their genetic material is DNA, which is found in chromosomes.

The DNA is all tangled up around histones.

If we remove the histones, here we can see the DNA.

In a normal colon cell, there is a balance between what's called histone acetylation and histone methylation.

Histone acetylation means that there is a better access for transcription factors to the DNA,

histone methylation means that there is decreased access for transcription factors to the DNA.

So, there is regression.

Therefore, if there is a lot of methylation, certain genes may not be activated.

So, looking at the histones here, we have a balance between histone methylation, ME,

and histone acetylation, AC.

Now, an important enzyme to know is HDAC, which is histone deacetylase.

This enzyme essentially removes an acetyl group from the histone.

So, here, the enzyme is removing the acetyl group from this histone.

And, HDAC is an important enzyme in decreasing access for transcription factors, essentially.

Now, along the DNA, there are regions called promotor regions and non-promotor regions.

Promotor regions are regions in the DNA that initiate transcription of particular genes,

meaning the synthesis of RNA.

Therefore, non-promotor regions are regions that contain no functional genes.

In a normal cell, colon cell, there is approximately 70-80% methylation in non-promotor regions.

But, around the promotor regions, genes are usually unmethylated.

And there is better access for transcription factors to activate genes.

And we will see the changes that occur in methylation as cancer develops.

Now, in 80% of cases of colon carcinogenesis, there is an adenomatous polyposis coli gene mutation

or APC gene mutation.

The APC gene is essentially a tumour suppressor gene,

because normally it encodes for proteins involved in cell adhesion and transcription.

This APC mutation can result in one of the stem cells to become potentially cancerous.

And so, as the abnormal cell, the potential cancer cell, moves up,

it will begin dividing and dividing,

creating a polyp, which is usually a small benign growth.

However, with more mutations, such as in 50-60% of colon cancer cases, there is

activation of the K-RAS oncogene,

as well as more mutations of other tumour suppressor genes.

Now, the K-RAS gene normally controls cellular division.

However, a mutation of the K-RAS gene results in a K-RAS oncogene,

and thus cell proliferation.

The cells will begin to proliferate.

This will create an adenoma, which is a larger benign growth.

During this time, as the cells keep dividing,

there needs to be more blood supply, in order to feed the growing tissue.

So, angiogenesis, which is formation and maturation of blood vessels, occur.

It should be noted that from when the potential cancer cell, the abnormal cells develop,

there can be a mismatch repair gene inactivation,

as well as hypermethylation occurring on the DNA.

The mismatch repair gene normally repairs mutations that occur in the genes,

hypermethylation silences genes.

Both mismatch repair gene inactivation and hypermethylation

can result in mutation rates that are a hundred time fold greater

than mutation rates that occur in normal cells,

which is a lot of mutations.

A mutation at the p53 gene tends to occur later in colon carcinogenesis.

This mutation will cause resistance of cancer cells to apoptosis.

So, more cells will divide, and less will die.

This will cause a massive growth, which will cave in

and keep growing, resulting in carcinoma, which is a malignant growth.

Now that we're at this stage, let us look at the genetic material of this cancer cell.

So here we have the chromosome again;

the histone fibres and the histone, and then the DNA.

The DNA which has, remember, the promotor and non-promotor regions.

In cancer cells, there is a disbalance between histone acetylation and histone methylation.

So we see more methylated histones.

Remember, methylation decreases access to transcription factors.

One reason why we see more methylation is because of HDAC, the enzyme

which appear to be more active in colon cancer cells.

So here, HDAC is removing all the acetyl groups on histones,

resulting in more methylated histones.

In colon cancer cells, we also see changes in DNA methylation.

In promotor regions, for example, there is usually hypermethylation

particularly in tumour suppressing genes and DNA repair genes.

This results in some of the mutations we talked about earlier.

And in non-promotor region, there tends to be fewer methylation.

So again, there is hypermethylation on promotor regions,

which contributes to gene silencing and genomic instability,

and it will affect apoptosis, DNA repair, and cell-cycle control.

And there tends to be a decrease in methylation on non-promotor regions, which essentially don't do anything.

I hope you enjoy this video on colon cancer carcinogenesis. Thank you for watching.