Grant: CIHR/Regional Partnership Program/Operating Grants

Our genetic material, DNA, is bound to proteins called histones which package the DNA. Modifications of the histones decide whether packaging of the DNA is "loose" allowing genes to be expressed or "compact" to silence the expression of genes. Dr. Davie's research team is investigating the processes by which the protein products of oncogenes (e.g. ras, a gene that when mutated changes a normal cell into a cancer cell) alter the modification of histones and induce the expression of genes involved in the formation of tumors. Ras, the protein product of the ras oncogene, sends unregulated signals from the cell surface into the nucleus, leading to increased modifications of several proteins including histones. Dr. Davie's research team has shown that cells expressing the ras oncogene have an increased level of phosphorylated histone H3 (a histone modification). The enzyme responsible for H3 phosphorylation is mitogen- and stress-activated kinase (MSK). The activity of this enzyme is regulated by growth factors, tumor promoters and oncogenes such as Ras. Dr. Davie found that MSK-mediated H3 phoshorylation is crucial for cancer cells to metatasize. Dr. Davie's research team is using normal-like (non-transformed) and cancer cell lines, which express the ras oncogene, to understand how MSK and histone H3 phosphorylation induce the expression of genes involved in tumor formation and metastasis. The studies will explore the importance of MSK in enabling cells to metastasize, providing a new therapeutic target in the treatment of cancer. Mutations in the ras gene are commonly found in cancer. In pancreatic cancer, about 95% of all diagnosed adenocarcinomas have an acquired mutation in the ras gene which leads to a constitutively activated oncoprotein. Dr. Davie's research will learn now these agents promote cancer, and with this knowledge understand how normal cells are changed to cancer cells and and reveal new therapeutic avenues in the treatment of cancer.