Beacons of life and death: chromatin and cancer

The basic functioning of our cells is governed by complex signalling pathways that relay what’s happening around and within cells to their control centre – the cell’s nucleus. The nucleus responds by regulating which genes in our DNA are switched on and off. When this fine-tuned regulation goes wrong, diseases such as cancer can result.

At the heart of this gene regulation are proteins called histones, around which DNA is wrapped rather like beads on a string, before being supercoiled into a structure called chromatin. But histones are not just a packing material. Histones also act as beacons, guiding enzymes to specific locations on the genome in order to turn genes on and off. Professor Tony Kouzarides’ research group at the Wellcome Trust/Cancer Research UK Gurdon Institute discovered in the 1990s that this process is governed by enzymatic machinery that modifies the histone proteins. Many of the pathways that lead to the modification of histones are deregulated in cancer.

Professor Kouzarides’ latest discovery, in collaboration with Professor Tony Green’s group in the Department of Haematology, has made a crucial link between a faulty histone-modifying enzyme and leukaemia.

New route to leukaemia

The research, funded by Cancer Research UK and published recently in Nature, was carried out by Dr Andy Bannister and PhD student Mark Dawson. They studied an enzyme known as Janus kinase 2 (JAK2), which functions as a signal transducer – essentially, a component of the cell’s signalling pathways that converts one type of signal to another. Faulty JAK2 has been linked with leukaemia for a number of years.

The breakthrough came when the scientists found an unknown signalling function of JAK2. Previously, JAK2 had been thought to transduce signals only within the main part of the cell, but the researchers showed that it can enter the nucleus and modify histones. Importantly, they discovered that the modification normally switches on a gene that causes leukaemia, and makes it remain on constantly. The researchers had uncovered a direct mechanistic link between a signal transducer, histone modification and cancer.

Towards therapeutics

The goal now is to continue their ongoing search for other enzymes that modify histone proteins (the group has discovered several already). Professor Kouzarides believes that these hold the key to a future generation of cancer therapeutics. A University spin-out, Chroma Therapeutics, was launched in 2001 to exploit his research and that of others in the chromatin field, with the aim of harnessing the new understanding of chromatin biology to develop novel therapeutics to prevent, diagnose and treat cancer.

Leaps in understanding the basic molecular genetics that control and disrupt cell function are bringing a new generation of therapeutics closer. Just as histone proteins act as beacons for drawing signalling enzymes towards DNA, they are also beacons for cancer researchers intent on increasing the arsenal of anticancer therapeutics.

For more information, please contact Professor Tony Kouzarides (t.kouzarides@gurdon.cam.ac.uk), the Royal Society Napier Professor, at the Wellcome Trust/Cancer Research UK Gurdon Institute. This research was published in Nature (2009), 461, 819–822.