Tumor Genetics Blog

By: Joonas Uusi-Mäkelä

Suomennos: Tilaa paranemiselle – miten kromatiinin avoimuus muuttuu eturauhassyövässä?

Prostate cancer is the most common cancer among men in western countries. Luckily it is often diagnosed as a primary cancer at older ages, when it has no negative effect on life expectancy. However, in some cases disease has progressed and needs treatment. Treatment is usually effective for a while, but sooner or later treatment effectiveness goes down, leading to so-called castration resistant prostate cancer (CRPC), which is incurable. As a result, prostate cancer is the second most common cause of cancer deaths among men in western countries.

The starting point for our study is to find out what happens in the cells first when normal prostate cells develop into primary cancer, and then when primary cancer develops into CRPC. A unique feature in our study is that we have a sample set collected from patients which includes benign prostatic hyperplasia, primary tumors and CRPCs. With this set we can study what changes take place in the cells during different stages of cancer development. Another unique feature of our study is that the data represents the accessibility of chromatin. Changes in chromatin accessibility during the development of different stages of cancer have not been studied so far in detail.

What is meant by chromatin accessibility?

Imagine that you are in a big festival, where there is a large crowd of people watching a popular artist. You are separated from your friend and are trying to find him to tell him that you need to leave. You can see your friend as he is tall but there are too many people packed too tightly between you and him, so you can’t reach him. A similar situation is taking place in our cells.

In each of our cells there are DNA molecules carrying all our genetic information. These molecules, if opened as a straight strand, would be about two meters long. This means that DNA needs to be effectively packed to fit into our cells. All the time there are also a bunch of different proteins bound to DNA, and this combination of DNA and proteins is called chromatin. Some of these proteins have a special task of regulating the activity of genes in the DNA. To be able to do that they need to be able to bind specific locations of DNA. Sometimes they face the same problem as in the festival: there is not enough room to reach the correct binding spot because the chromatin around it is too closed.

What happens to chromatin accessibility as cancer develops?

In our study we find that changes in chromatin accessibility happened mostly in the areas where these regulatory proteins bind. This was interesting as we were expecting more changes to take place in the genes themselves, but, indeed, they were more often seen in regulatory regions. We also studied what kind of regulatory proteins then want to bind to these areas where accessibility changes. The group of different regulatory proteins that can bind DNA and alter gene expression is a large one. We started with proteins that we know, based on previous studies, are important for normal prostate cells and prostate cancer. We saw that in almost all the regions (over 95%) that were opening in the primary tumor there were binding sites for androgen receptor (AR) and FOXA1. Out of these two, FOXA1 is interesting, because it is known that it can open the chromatin for other proteins to bind. Also, AR is known to be highly important for prostate cancer to grow so it is not surprising that we see an increase in the open AR binding sites.

Let’s go back to the festival example. You still want to get to your friend. Another friend of yours arrives at the scene. He is big and strong and can move in the crowd without any problems. He starts to make his way towards your other friend, and this also opens a way for you to reach that friend. Now you can deliver your message to your friend. In a similar manner, FOXA1 opens the chromatin in prostate cancer and allows AR to bind these newly opened sites. One difference compared to the festival example is that, in cells, these chromatin sites mostly stay open after opening, and proteins, including AR, can continuously bind to these sites.

What happens to chromatin accessibility as cancer advances?

We were also interested in what the changes are when a primary tumor develops into CRPC. To our surprise, findings were almost opposite to those we got when studying the development of primary cancer. In almost all the regions (over 95%) that were closing in CRPC there were binding sites for AR and FOXA1. On the other hand, when considering opening sites, there are AR and FOXA1 sites only in about 50% of sites. So, it seems that sites opening in CRPC are more than just those sites that FOXA1 opens for AR. This begs the question, what are the proteins binding to these sites, and do they affect gene expression in a similar or different manner than well-studied AR does? Luckily, we also have data from other proteins, but at this stage things get more complicated. There are tens and tens of possible proteins that can bind to these sites.

Let’s return to the festival one more time. You still want to get to your friend, but this time there are also several other friends present in the crowd. You would like to talk to all of them at some point. Some of these friends are closer and easier to reach than others. You also have more important matters to discuss with some of your friends. Maybe your strong friend can help you move through the crowd to some of your friends but not others. It is also possible that when you talk with one friend, he or she goes to talk with someone else and this changes where everyone is and what they are doing. This creates a network where everything affects everything in which changes are regulated by who can reach whom through the crowd.

Where can we go from here?

We face a similar situation in our study. We have a large group of regulators that can bind the opening regions in CRPC, which then affect a large number of genes, which can then, in turn, affect these regulators. All this forms complicated network structures, which we are trying to unravel. Our aim is that these new findings regarding chromatin accessibility would give new tools to scientists to find treatment options for prostate cancer. We have already found that, although AR seems to be less important in CRPC, the group of genes regulated by AR in primary cancer is mostly the same as the one regulated by other proteins in CRPC. By affecting these genes, we could achieve treatment responses in CRPC as well.

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