Mechanistic Analysis of ARID Mutations in Hepatocellular Carcinoma
Abstract
Approximately 6 feet of DNA is packaged into every cell in the human body. Using proteins called histones, the DNA is packaged into an orderly complex called chromatin. While the main function of chromatin may be to allow the physical allocation of DNA into such a confined space, an important side effect of this structure is the potential for regulatory information. Mutations in the genes that regulate chromatin are frequent in many cancers. One family of genes that are frequently mutated are chromatin remodeling complexes. They consist of around 10 subunits, and they physically rearrange the DNA and chromatin. Mutations in chromatin remodeling complexes are particularly frequent in liver cancers, where three subunits of the SWI/SNF chromatin remodeling complex are mutated. These subunits each contribute to only one form of the complex, and their inclusion is mutually exclusive and they define distinct compositions of SWI/SNF. In cell lines mediate distinct functions, yet it remains unclear how the composition of the SWI/SNF chromatin remodeling complex contributes to cancer. Understanding their role in liver cancer is critical for developing new therapeutic strategies that target tumors with mutations in these genes. Dr. Raab is beginning a career that focuses on understanding the mechanistic underpinnings of chromatin disruption in cancer. His driving goal is to target tumors with disrupted chromatin as a new therapeutic strategy. His previous work laid a foundation for these studies by developing tools and methods to carefully dissect the role of chromatin remodeling in gene regulation. In the career development supported by this award he will take the next steps to applying these studies to a critical biological need and begin studies to generate new tumor models dependent on mutations in chromatin genes. The work proposed in this study will be the first direct comparison of multiple chromatin remodeling mutations in cancer and is form the basis for his independent lab. Currently, there are no therapies targeted specifically at tumors with mutations in chromatin remodeling genes. Given their prevalence, particularly in liver cancer, it is a critical need to develop specific therapies. A first step in achieving that goal is to understand how these genes contribute to the development of cancer and to generate new models in which we can study possible therapies. The proposed work addresses these two goals by answering whether each mutation within one chromatin remodeling complex function the same way. Additionally, this work will rapidly develop new mouse models of liver cancer by a massively parallel approach that allows the co-mutation of a gene alongside a mutation in SWI/SNF. These models will be characterized in this study, and future work will be developed to identify therapies targeting these models based on the work in this grant. This proposal addresses the Topic Area of Liver Cancer. Liver cancer is the ultimate outcome of a progressive disease caused by a variety of injuries to liver, including viral hepatitis, alcohol use, diet, and other liver toxins. Hepatitis C is found at in the Veteran population at a rate of approximately five times that in the general population. This is possibly due to many factors, including methods of vaccination, blood transfusions, and shared personal items. Incidence is highest among soldiers who served in Vietnam. However, viral hepatitis is not the only cause of liver cancer that affects the service-member population. Other causes of liver disease, including alcohol exposure, non-alcoholic fatty liver disease, and exposure to hepatotoxins that can also disproportionately affect members of the military. Based on sequencing of liver tumors, mutations in chromatin remodeling genes do not appear to be specific to any etiology of cancer. Our study will provide fundamental data about how disruption of chromatin contributes to liver cancer and will point to specific treatments for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910423
Entities
People
- Jesse R Raab
Organizations
- United States Army
- University of North Carolina at Chapel Hill