Chromatin Dysregulation and Metabolism Disorder in Kidney Cancer
Abstract
There are an estimated 400,000 people in the United States living with kidney cancer and many more worldwide. The majority of these cases are clear cell renal cell carcinoma (ccRCC). Despite recent advances in treatment, metastatic ccRCC remains largely incurable. Because of environmental exposure, military personnel and Veterans experience an overall fivefold to sixfold increased incidence of ccRCC over the general population. The goal of our studies is to gain a more comprehensive understanding of ccRCC biology in the hopes of improving diagnostics and treatment for patients with ccRCC. Kidney cancer is thought to be a metabolic disease because of the high mutation rate of genes involved in metabolic stress and nutrient sensing. In addition, mutations in genes that code for chromatin-associated proteins have recently been identified in kidney cancer. Chromatin-associated proteins are also known as epigenetic regulators because they allow cells to alter gene expression profiles in response to environmental signals. One of these genes, SETD2, is mutated in ~15% of ccRCCs. The main known function of SETD2 is to chemically modify chromatin, but the biological importance of this modification is unclear. We think that one outcome of SETD2 activity might be to directly connect metabolism and gene regulation and that loss of SETD2 might alter cellular responses to metabolic stress. We will test this hypothesis using kidney cancer cells that either express SETD2 or have lost this gene, taking advantage of a variety of molecular, cell biology, and genomics techniques to do so. Our work represents two of the FY17 KCRP Areas of Emphasis: (1) Chromatin and Gene Regulation and (2) Metabolism. These studies are innovative because they link two spheres of biology that are studied distinctly, yet are inextricably linked. The proteins that modify chromatin use metabolites that are produced by cells to do so. Yet, people who study chromatin rarely study the generation of these metabolites, and people who study metabolism often do not study how these metabolites regulate chromatin. This proposal will link these two fields to improve our understanding of the initiation and progression of kidney cancer. Further, our work will attempt to identify new therapeutic targets for kidney cancers carrying SETD2 mutations. If successful, these studies could have profound impacts on the way that we understand kidney cancer. These studies will link chromatin regulation to the metabolic state of cells and their sensitivity to stressful environments. They represent a novel outlook and approach and may improve our ability to diagnose and treat this disease. This is important for Service members and Veterans, who suffer a higher incidence of kidney cancer, and also for the American public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810670
Entities
People
- Laura A Banaszynski
Organizations
- United States Army
- University of Texas Southwestern Medical Center