Chromatin and Cancer

Proteins are the things in our cells that make it happen. Proteins come in all shapes and forms, some work as monomers, some as huge multi-subunit complexes. They are important for catalysing a whole range of different reactions that are essential for the cell's survival and its effect on the cells around it, which in turn can have systemic implications depending on the tissue the cell is found in.
So you can imagine that protein synthesis must be a tightly controlled process and that mistakes can result in disease, one of which is cancer - the uncontrolled proliferation of cells to form a tumour.

Cancer is a disease that is caused by many different defects, some of which can be inherited or induced by environmental influences, such as an unhealthy lifestyle or exposure to carcinogenic substances. In many cases, cancers are multifactorial, i.e. many different factors come together to predispose a person to cancer and finally to initiate tumorigenesis. 

In order to control growth and division, a cell has a number of intricate mechanisms in place that make sure the cell only divides after its DNA has been correctly replicated, and that the environmental conditions are favourable for growth. Mutations in genes that code for proteins involved in these processes can lead to cancer, as the controlling elements are taken away and the cell undergoes multiple rounds of replication unchecked.

A group of genes identified as having a central role in the prevention of cancer, are the tumour suppressor genes. These code for proteins that in some way provide a check in the cell's replication machinery to stop progression from normal cell growth to uncontrolled proliferation. An example of this is p53, also known as the "guardian of the genome" because of its central role in many crucial processes overseeing cell survival and cancer prevention. 

Therefore, cancers can be formed due to mutations in these proteins, but in general, tumorigenesis can often occur due to the synergic effect of many different factors. In the last few years, it has become apparent that chromatin remodelling may play an important role in initiating cancer and determining tumour progression (1). 

Chromatin is a structure made up of individual proteins called histones that coats DNA in such a way as to condense it in the cell nucleus and can control gene transcription by for example obstructing or opening up binding sites for proteins involved in the inititation of transcription on the DNA template. This remodelling of chromatin is performed by special proteins termed "ATP-dependent remodelling complexes". 

One example is the SWI/SNF complex, which is found in many eukaryotic cells, including yeast, fly and human cells. This is an example of a large mutli-subunit protein that is made up of an ATPase subunit (the molecular motor of the complex), three core subunits and a range of accessory subunits. The ATPase contains a Bromodomain, a region of the protein that recognises a certain chemical group on the histones in chromatin (an acetyl-group), and therefore, once the histone has been modified to display this chemical group (i.e. has been acetylated), SWI/SNF binding to the chromatin can be stabilised via interactions between the Bromodomain and the acetyl-group on the chromatin (2). Now this is the cool bit: SWI/SNF moves along the DNA (this is why it needs the ATPase, i.e. the molecular motor - it needs energy to move and this is supplied in the form of ATP) and changes the position of the chromatin subunits (called nucleosomes - these are made up of 8 histone proteins) so as to leave a part of the DNA uncovered and accessible to other proteins that can then bind and start transcribing the DNA to make a copy of the gene of interest that can be sent outside the nucleus and then used to make a new protein. 

What has all of this got to do with cancer? Well, researchers have found that in a number of cases, cancerous cells have SWI/SNF complexes that are not normal. For example, they may be missing one of their subunits (as is the case in many Malignant Rhabdoid Tumours, where the core subunit SNF5 is defective (1)), or they may have a different combination of subunits that changes their function slightly and makes them more able to contribute to tumour formation (1). 

Abnormal SWI/SNF could for example fail to uncover the right part of DNA needed for a tumour suppressor gene to be transcribed and therefore help break down the cell's protective mechanisms against cancer formation. 

As you can see, it is hard to remain within one area when looking at the body and how mechanisms are affected in disease to bring about an abnormal state, because the mechanisms all work together to make up an intricate network of interactions. Like in a chain, if one of the links breaks, the whole chain opens up and is broken. The same is true for many disease states and the challenge is to find the "weak link", so as to be able to target it in some way in a hope of curing the disease.

References:

(1) Weissman B, Knudsen K E (2009), "Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Pertubations in Cancer", Cancer Research 69 (21): 8223-8230

(2) Hassan A H, Prochasson P, Neely K E, Galasinski S C, Chandy M, Carrozza M J, Workman J L (2002), "Function and Selectivity of Bromodomains in Anchoring Chromatin-Modifying Complexes to Promoter Nucleosomes", Cell 111: 369-379