Breakthrough discovery into the regulation of a key cancer drug target

July 1, 2013
Inositol phosphates are small molecules that act as a key to regulate the activity of histone deacetylase enzymes. These enzymes are emerging as important drug targets for diseases such as cancer and Alzheimer's. Credit: University of Leicester

There's not much difference between what makes a man and what makes his beer - at least at the molecular level - according to a new study led by Professor John Schwabe at the University of Leicester.

Scientists used a powerful technique called to look at 3D structures of protein complexes purified from . They discovered that a family of complexes, that switch off , is regulated by small signalling molecules called inositol .

This latest study shows that this mode of regulation is conserved from yeast right through to man and is a fundamental process for life.

This discovery is potentially important for developing anti- since these complexes are emerging as effective targets.

The research was funded by the Wellcome Trust and involved collaboration with scientists from the University of Oxford. It was published online ahead of print (July 11) in the journal Molecular Cell.

The importance of this work is emphasised by the award, in November 2012, of £2.4 million in the form of a prestigious "Wellcome Trust Senior Investigator Award" to Professor John Schwabe to continue and develop this area of research.

Professor Schwabe said: "Gene regulation is an essential that occurs in every cell in the body to control which proteins are expressed in particular tissues. We have been studying enzymes called Histone Deacetylases (HDACs) that regulate this process. The action of HDACs causes the DNA to become more tightly packaged and thus switches off genes by making them unavailable for expression. HDACs are recruited to DNA by a number of accessory proteins (corepressors) that target the to the correct gene."

In 2012, the research team announced in Nature that they had discovered a completely new and unexpected mechanism through which one particular HDAC complex (HDAC3 bound to its companion protein SMRT) is regulated.

Professor Schwabe said: "We wanted to ask whether this mode of regulation might apply to other HDAC complexes and be a general principle for HDAC regulation. Now we have taken this investigation several steps forward.

"We have solved the first structure of HDAC1 bound to one of its corepressor proteins (MTA1 – Metastasis-associated protein 1). This new structure allows us to examine how the proteins interact at the atomic level and reveals molecular details that have allowed us to probe the interaction surface.

"We have identified that there is an inositol phosphate-binding site at the interface between the two proteins, and through functional studies, we have confirmed that inositol phosphates are key regulators throughout this class of enzyme.

"This establishes that inositol phosphate regulation is a general paradigm that is conserved from yeast to man. In addition, we have shown that two MTA1 molecules come together to recruit two HDAC enzymes, and we suggest that MTA1 is critical for recruiting HDAC1 to DNA."

Professor Schwabe also emphasised that his research team is very privileged to have secured further funding from the Wellcome Trust to support this programme of research for the next 7 years: "We expect to gain an in depth insight into the role of inositol phosphates in the regulation of class I histone deacetylases and the specificity conferred to histone deacetylases by their recruitment into large multi protein complexes".

The research team used a cutting edge technique (protein crystallography) to look at the 3D structure of proteins involved in . They optimised the conditions needed to grow microcrystals and took these to the UK's powerful synchrotron (Diamond Light Source, Oxford) to obtain diffraction data. These data are used to build images of the proteins, and for the first time, the team has been able analyse how the proteins interact with each other.

"With this new level of molecular detail we are exploring the design of novel HDAC inhibitors to target of the HDAC-corepressor interface. These may provide the foundation for future drug development and may lead to new anti-cancer therapies".

Explore further: Unexpected discovery opens up new opportunities for targeting cancer

Related Stories

Tweaking gene expression to repair lungs

February 25, 2013

A healthy lung has some capacity to regenerate itself like the liver. In COPD, these reparative mechanisms fail. HDAC therapies may be useful for COPD, as well as other airway diseases. The levels of HDAC2 expression and ...

Recommended for you

We've all got a blind spot, but it can be shrunk

August 31, 2015

You've probably never noticed, but the human eye includes an unavoidable blind spot. That's because the optic nerve that sends visual signals to the brain must pass through the retina, which creates a hole in that light-sensitive ...

Biologists identify mechanisms of embryonic wound repair

August 31, 2015

It's like something out of a science-fiction movie - time-lapse photography showing how wounds in embryos of fruit flies heal themselves. The images are not only real; they shed light on ways to improve wound recovery in ...

New 'Tissue Velcro' could help repair damaged hearts

August 28, 2015

Engineers at the University of Toronto just made assembling functional heart tissue as easy as fastening your shoes. The team has created a biocompatible scaffold that allows sheets of beating heart cells to snap together ...

Fertilization discovery: Do sperm wield tiny harpoons?

August 26, 2015

Could the sperm harpoon the egg to facilitate fertilization? That's the intriguing possibility raised by the University of Virginia School of Medicine's discovery that a protein within the head of the sperm forms spiky filaments, ...

Research identifies protein that regulates body clock

August 26, 2015

New research into circadian rhythms by researchers at the University of Toronto Mississauga shows that the GRK2 protein plays a major role in regulating the body's internal clock and points the way to remedies for jet lag ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.