Young Investigator Highlight: George Souroullas:

NOVEL CHROMATIN EFFECTS OF ONCOGENIC EZH2 MUTATIONS

In the last few years the cancer genome atlas (TCGA), has allowed us to identify numerous cancer-associated mutations.

What is the Cancer Genome Atlas / TCGA (cancer.gov): TCGA is a project to identify the complete set of DNA changes in many different types of cancer. Studying these changes may help researchers understand how different types of cancer form. This may lead to new ways to prevent, diagnose, and treat cancer. TCGA is led by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), which are parts of the National Institutes of Health (NIH). Also called The Cancer Genome Atlas.

This information is critical, both in terms of disease prognosis, but also in the identification of novel therapeutic targets and for fulfilling the promises of personalized medicine. Sequencing studies from the TCGA have also highlighted the central role of epigenetic processes in cancer causation and progression and treatment. This presents us with a remarkable opportunity in translational medicine because, unlike DNA mutations, these epigenetic modifications are reversible and can be targeted by small molecule inhibitors.

Dr. Souroullas and his lab focus on molecular mechanisms and mutations in epigenetic regulators that contribute towards cancer development and which are also potential therapeutic targets. More specifically, Dr. Souroullas proposes to focus on the chromatin modifying enzyme EZH2 and to use basic scientific approaches to uncover how misregulation of EZH2 changes cells and allows them to become cancerous.

What is EZH2? (via NIH): The EZH2 gene provides instructions for making a type of enzyme called a histone methyltransferase. Histone methyltransferases modify proteins called histones, which are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a molecule called a methyl group to histones (methylation), histone methyltransferases can turn off (suppress) the activity of certain genes, an essential process in normal development. Specifically, the EZH2 enzyme forms part of a protein group called the polycomb repressive complex-2. By turning off particular genes, this complex is involved in the process that determines the type of cell an immature cell will ultimately become (cell fate determination).

The proposal will also investigate how misregulation of EZH2 cooperates with genetic mutations in other chromatin modifying genes, with the overall goal of understanding how changes in chromatin dynamics lead to the development of cancer.