Targeting cancer’s self-defence mechanisms

Dr John Halsall and Professor Bryan Turner, from the Chromatin and Gene Expression Group at the University of Birmingham, write about their latest research.

We often talk about cancer as being a disease caused by mistakes in DNA – the genetic instructions inside all our cells that tell them to make molecules such as proteins. And faulty genes do indeed cause cells to grow out of control, leading to cancer.

It isn’t just the sequence of the DNA that matters, but also how it’s used that’s important: all the billions of cells in our bodies have the same set of 20,000 or so genes, yet a skin cell is very different from a kidney tubule or a heart muscle cell.

This is because each type of cell turns on a distinct set of genes, producing the right combination of proteins needed by that particular cell type. For example, skin cells make lots of keratin (a tough molecule that keeps our skin strong), while nerve cells produce the chemical signals that enable them to ‘talk’ to each other and transmit information.

The new science that studies the ways in which cells control their gene activity patterns – and adapt them in response to their environment – is known as epigenetics. This is now a hot topic for many researchers around the world, including our Cancer Research UK-funded lab at the University of Birmingham.

Epigenetics: what’s it all about?

We now know that genes can be marked as being switched on or off using a series of chemical tags, either directly attached to DNA (known as DNA methylation) or to the histone proteins that package it.

There is growing evidence that changes to both of these types of tag can occur in cancer cells, alongside alterations to the underlying DNA instructions. In turn, these epigenetic changes might affect gene activity patterns, helping to drive cancer growth.

As a result, there’s a lot of interest in developing cancer drugs that target these modifications, as well as the molecules that put them on (or take them off).

Some of these treatments – such as azacytidine (Vidaza), which affects DNA methylation patterns – have recently shown promise in several types of cancer (although it appears that they may work by tricking cells into thinking they’re infected with viruses).

But there’s still a lot that we don’t understand about exactly how epigenetic drugs affect cancer cells, and why their effects vary between different types of cancer or even different patients with the same type of cancer.

Hanging in the balance

Our group is particularly interested in one particular epigenetic tag, known as histone acetylation, which generally occurs around active genes.  Acetylation is thought to ‘loosen up’ the histone packaging in that region of DNA, providing easier access for the cell’s gene-reading machinery, and attracting other proteins that help to switch genes on.

The level of histone acetylation around a gene is controlled by the opposing actions of two types of proteins. One group is called lysine acetyltransferases (KATs*) which put on acetylation marks. The others, which remove them, are known as histone deacetylases (HDACs).

Chemicals that interfere with HDACs – known as HDAC inhibitors – alter this delicate balance, leading to a rapid increase in histone acetylation. So, unsurprisingly, there’s a lot of interest in testing whether HDAC inhibitors can reverse the gene activity changes that contribute to cancer.

HDAC inhibitors have shown some promise, particularly against blood cancers, but there’s a lot of variability in response. Some patients do better than others, and they only seem to work against a few types of cancer.

Adding to this confusion, it’s not just HDAC inhibitors – which increase a cell’s levels of histone acetylation – that have anticancer effects. It turns out that drugs that act as KAT inhibitors – which shift the balance the other way, and lead to a drop in acetylation levels – sometimes seem to work too.

So it’s clear that we need to do more to understand how epigenetic drugs are targeting cancer, in order to work out how best to use them.

In a new paper from our team, published in the journal Epigenetics and Chromatin, we’ve been investigating how cells respond during the very early stages of exposure to HDAC inhibitors.

Importantly, we’ve discovered that cells can activate a ‘self-defence’ response against them, which must be overcome if epigenetic therapies are to be effectively used to treat cancer in the future.

Keep calm and carry on…

At the heart of our study is a long-standing puzzle: despite the fact that many experiments have shown that HDAC inhibitors can affect a cell’s epigenetic control systems, human cells survive this challenge very well, both in the laboratory and in the real world.

For example, bacteria in our large intestine produce large amounts of a chemical called butyrate, which is an HDAC inhibitor. Yet despite being bathed in butyrate, the cells in our gut can cope just fine.  The reasons behind this indifference are a mystery.

Because HDAC inhibitors rapidly cause an increase in histone acetylation (which switches genes on), it might be expected that treatment with these drugs would lead to a burst of out-of-control gene activity. Instead, when we added different doses of HDAC inhibitors to normal human cells growing in the lab, we found that only a small proportion of genes changed their activity levels.

Intriguingly, many of these genes turned out to be part of an emergency survival response, kicking in within 30 minutes of adding the drug. For example, some of them send signals that slow down cell growth, while others prevent cells from dying.

We also saw that levels of KAT activity were reduced, counteracting the effects of blocking HDACs.

Overall, this suggests that cells are managing to ‘buffer’ the drug’s impact, meaning that HDAC inhibitors seem to cause relatively few changes in histone acetylation patterns in and around genes.

Our work shows, for the first time, that when normal human cells are exposed to HDAC inhibitors, they rapidly reorganise their patterns of gene activity so as to minimise the immediate effects of the drugs. This switches cells into a kind of self-defence mode, meaning that they can survive and keep growing despite the epigenetic changes induced by the treatment.

Where next?

Given that HDAC inhibitors do work against certain types of cancer – notably lymphomas – we think these cancers must be inherently sensitive to the drugs because their survival response has already failed. For example, perhaps the genetic and epigenetic changes that are driving these cancers to grow have also impaired their ability to activate their self-defence system.

As we continue to study the epigenetic survival response in cancer cells, we hope to identify the key genes that control it. These could then be used as markers to identify cancers that are likely to respond to treatment with HDAC inhibitors or other epigenetic modifying drugs.

Or it could lead to the development of future therapies that override the self-defence mechanisms in tumour types that don’t respond to these drugs.

And, ultimately, combining HDAC inhibitors with drugs that undermine the survival response specifically in cancer cells may open the way to life-saving treatments in the future.

John and Bryan

Reference:

J. A. Halsall, N. Turan and B. M. Turner. Cells adapt to the epigenomic disruption caused by histone deacetylase inhibitors. Epigenetics & Chromatin (2015)

*In case you’re wondering, lysine acetyltransferases are called KATs because the letter K is usually used to denote the amino acid lysine.