Mechanisms of DNA methylation signaling and dysregulation in colon cancer

PROJECT SUMMARY Colon cancer is a leading cause of cancer-related death for both men and women in the United States. Abnormal DNA methylation patterning is an epigenetic hallmark of colon and other cancer types and is a major contributing factor to genome instability and tumor suppressor gene silencing in this disease. Despite a deep appreciation of roles for DNA methylation in development and cancer, causal mechanisms that contribute to the evolution of DNA methylation abnormalities in colon and other cancer types, and consequences of this hallmark epigenetic remodeling on cancer development, remain poorly understood. This proposal seeks to address these fundamental knowledge gaps. Our preliminary data implicate protein ubiquitination as an essential post- translational modification (PTM) regulating the activity of DNMT1, the primary enzyme responsible for the epigenetic inheritance of DNA methylation patterns through mitotic cell divisions and a major target for epigenetic cancer therapy. Building from these data, studies in Aim 1 will characterize the ubiquitin signaling network that interfaces with DNA methylation inheritance. The therapeutic potential of targeting ubiquitin signaling regulators in this pathway will also be considered. In Aim 2, we will test a mechanistic hypothesis connecting overexpression of the E3 ubiquitin ligase UHRF1 to DNA methylation dysregulation and colon tumorigenesis. Aim 3 will investigate a non-canonical function for UHRF1 in the regulation of heterochromatic histone PTM signaling and its implications for DNA hypomethylation therapy. Overall, our studies at the interface of ubiquitin signaling and DNA methylation inheritance will reveal fundamental causes and consequences of abnormal DNA methylation signaling in colon cancer and identify novel approaches to enhance the efficacy of DNA hypomethylation therapy as a treatment strategy to manage this deadly disease.