The Epigenetics Revolution

You don’t need a chemistry degree to see that TSA and SAHA look fairly similar, especially at the right hand side of each molecule. Victoria Richon hypothesised that, just like TSA, SAHA was also an HDAC inhibitor. In 1998, she and her colleagues published a paper that showed this was indeed the case[179]. SAHA prevents HDAC enzymes from removing acetyl groups from histone proteins, and as a result, the histones carry lots of acetyl groups.

Beyond coincidence

So, 5-azacytidine and SAHA both decrease cancer cell proliferation, and both inhibit the activity of epigenetic enzymes. Although we could take this as promising support for the theory that epigenetic proteins are important in cancer, perhaps we could just be leaping to conclusions? It might just be a coincidence that both drugs affect epigenetic proteins. After all, the enzymes targeted by the two compounds are very different. 5-azacytidine inhibits the DNMT enzymes, which add methyl groups to DNA. SAHA, on the other hand, inhibits the HDAC family of enzymes, which remove acetyl groups from histone proteins. Superficially, these seem like very different processes. Maybe it’s just coincidence that both 5-azacytidine and SAHA inhibit epigenetic enzymes?

Epigeneticists believe that it is far from being a coincidence. DNA methyltransferase enzymes add a methyl group to the cytidine base. High concentrations of this base are found in the long CG-rich stretches of DNA known as CpG islands. These islands are found upstream of genes, in the promoter regions that control gene expression. When the DNA of a CpG island is heavily methylated, the gene controlled by that promoter is switched off. In other words, DNA methylation is a repressive modification. DNMT activity increases DNA methylation and therefore represses gene expression. By inhibiting these enzymes with 5-azacytidine, we can drive gene expression up.

Histone proteins are also found at the promoters of genes. Histone modifications can be very complex, as we saw in Chapter 4. But histone acetylation is the most straightforward in terms of its effects on gene expression. If the histones upstream of a gene are heavily acetylated, the gene is likely to be highly expressed. If the histones are lacking acetylation, the gene is likely to be switched off. Histone deacetylation is a repressive change. Histone deacetylases (HDACs) remove the acetyl groups from histone proteins and will therefore repress gene expression. By inhibiting these enzymes with SAHA, we can drive gene expression up.

So there is a consistent finding. Our two unrelated compounds, which control growth of cancer cells in culture and which have now been licensed for use in human treatment, inhibit epigenetic enzymes. In doing so, they both drive up gene expression which raises the obvious question of why this is useful for treating cancer. To understand this, we need to get to grips with some cancer biology.

Cancer biology 101

Cancer is the result of abnormal and uncontrolled proliferation of cells. Normally, the cells of our body divide and proliferate at exactly the right rate. This is controlled by a complex balancing act between networks of genes in our cells. Certain genes promote cell proliferation. These are sometimes referred to as proto-oncogenes. They were represented by a plus sign in the see-saw diagram in the previous chapter. Other genes hold the cell back, preventing too much proliferation. These genes are called tumour suppressors. They were represented by a negative sign on the same diagram.

Proto-oncogenes and tumour suppressors are not intrinsically good or bad. In healthy cells, the activities of these two classes of genes balance each other. But when regulation of these networks goes wrong, cell proliferation may become mis-regulated. If a proto-oncogene becomes over-active, it may push a cell towards a cancerous state. Conversely, if a tumour suppressor gets inactivated, it will no longer act as a brake on cell division. The outcome is the same in both cases – the cell may begin to proliferate too rapidly.

But cancer isn’t just a result of too much cell proliferation. If cells divide too quickly but are otherwise normal, they form structures called benign tumours. These may be unsightly and uncomfortable but unless they press on a vital organ and affect its activity, they are unlikely in themselves to be fatal. In full-blown cancer the cells don’t just divide too often, they are also abnormal and can start to invade other tissues.

A mole is a benign tumour. So is a little outgrowth in the inside of the large intestine, called a polyp. Neither a mole nor a polyp is dangerous in itself. The problem is that the more of these moles or polyps you have, the greater the likelihood that one of them will go the next step, and develop an abnormality that will take it further along the path towards full-blown cancer.