Gene-editing techniques give new insight on key protein involved in medulloblastoma development

Thursday 30 March 2017

Researchers at St. Jude Children's Research Hospital, USA have revealed how a key protein involved in driving the growth of the most aggressive form of medulloblastoma also plays a role in stopping its development.

This crucial protein, an enzyme called Ezh2, has previously been shown to help advance medulloblastoma growth. However, the results of this study show that the enzyme may also be acting to prevent tumour progression. This difference in function has potential implications for the use of drugs that are designed to stop the activity of this enzyme.

Medulloblastoma is the most common high grade brain tumour found in children, accounting for 15-20 per cent of all childhood brain tumours. Research has shown that this tumour can be divided into four subgroups with varying prognoses based on clinical, genetic and demographic differences. The most aggressive of the four are group 3 medulloblastoma tumours, some of which overexpress Ezh2.

Using a gene-editing tool called CRISPR, the team stopped the activity of this enzyme in the lab. CRISPR is a technique that has been hailed as a revolution in genetic engineering, consisting of a pair of 'molecular scissors' and a homing device to seek out a specific section of DNA so that it can be cut out. Loss of function of this protein using CRISPR resulted in acceleration of the development of medulloblastoma tumours, showing that Ezh2 was in fact acting as a suppression mechanism to halt tumour growth.

These findings now pose questions about the use of inhibitors to target this protein in a way that stops the progression of this tumour.

This research also revealed that there are a number of other genes involved in the development of medulloblastoma, including Myc, a well-known tumour-causing gene, and another protein called Gfi1. Knocking out the function of Ezh2 showed that Gfi1 sequentially talks to Myc to turn on pathways that promote tumour growth.

"Earlier work revealed that two genes, Gfi1 and Gfi1b, cooperate with Myc to promote the development of Group 3 medulloblastoma," said Paul Northcott, Ph.D., a study author and assistant member of the St. Jude Department of Developmental Neurobiology.

"The new study further substantiates the tumorigenic role of Gfi1 in medulloblastoma, and reveals that this oncogene is normally repressed by Ezh2. The loss of this regulation by Ezh2 'releases the brakes' on Gfi1 and leads to uncontrolled cell growth. The findings in the current study help refine our knowledge of some of the important molecular mechanisms involved in Group 3 medulloblastoma and will be useful for probing therapeutic potential."

Collectively, all of these findings describe how the activities of Ezh2, Myc and Gfi1 combine to drive group 3 medulloblastoma growth and point to future efforts directed to developing a further understanding of how these three key drivers specifically communicate with one another.

These findings will also be useful for helping to develop future drugs to target the genes that are implicated in the growth of medulloblastoma, providing the possibility of much needed therapeutic options for this devastating disease.