An international team of scientists led by the Peter MacCallum Cancer Centre and The Wistar Institute, USA, have discovered a new mechanism that fine-tunes gene expression.

The research is focussed on Protein Phosphatase 2A (PP2A), and has revealed the role it plays as a “brake” to oppose the activity of an enzyme called Cyclin Dependent Kinase 9 (CDK9) that drives gene expression.

Professor Ricky Johnstone, who is Peter Mac’s Executive Director of Cancer Research, and his team led the research along with Alessandro Gardini, Assistant Professor in the Gene Expression & Regulation Program at The Wistar Institute in Philadelphia.

“We know that altered gene expression is a hallmark of cancer," said Professor Johnstone. 

"We think our discovery provides new insight into how gene expression is tightly controlled."

The studies – performed by Peter Mac’s Dr Stephin Vervoort, a senior postdoctoral fellow in the Johnstone laboratory and the collaborative team - provide a new way of thinking about how altered gene expression in cancer occurs and how it may be rectified.

This fine balance between CDK9 and PP2A maintains appropriate gene expression levels in normal cells, and when this balance is affected one of the consequences is unrestricted gene transcription that can result in cancer onset and development.

“Cancer is a consequence of altered gene expression, as turning on or off one or more genes at the wrong time or in the wrong cells can dramatically alter their overall behaviour and lead to unrestrained growth,” said Assistant Professor Gardini, from the Wistar Institute.

The researchers also utilised new drugs targeting PP2A and CDK9 to reset unbalanced gene expression in cancer cells, resulting in death of the tumors and therapeutic benefit in preclinical models.

“This represents a completely new potential avenue for cancer treatment and initial studies suggest this could also improve the effect of another emerging treatment approach – CDK9 inhibition – in both blood-based and solid cancers,” said Professor Johnstone.

The research suggests PP2A and CDK9 work in tandem to fine-tune the balance between activation and inhibition of gene transcription. And a treatment that activates PP2A while inhibiting CDK9 could have a potent combined anti-cancer effect.

Read the paper titled “The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer” just published in Cell.

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Peter MacCallum Cancer Centre is a world-leading cancer research, education and treatment centre and Australia’s only public health service solely dedicated to caring for people affected by cancer.