How cell growth and proliferation are coordinated with metabolism and the metabolic state of a cell is an important unresolved question that is critical to understanding the metabolic alterations that contribute to cancer. Cancer cells frequently exhibit a highly glycolytic metabolism and consume substantial quantities of glucose to promote proliferation. However, the mechanisms by which glucose and carbon source availability are sensed by a cell as a measure of proliferative capacity remain controversial and poorly understood. Despite renewed interest in cancer metabolism, it has been unclear which aspect of cellular metabolism might represent a realistic, targetable vulnerability of tumors but not normal cells. We recently discovered that acetyl-CoA represents the key metabolite of carbon sources that functions as a critical metabolic signal for growth. Upon entry into growth, cells upregulate the production of acetyl- CoA which consequently induces the acetylation of histones specifically at those genes important for growth. As such, acetyl-CoA enables the expression of these growth genes and thus commitment to proliferation. Preliminary data suggest that a similar metabolic growth control mechanism exists in mammalian cells. These and other considerations have led to the realization that particular enzymes and proteins may play critical roles in fueling the acetyl-CoA- induced growth response pathway. The goal of this proposal is to comprehensively investigate the feasibility of targeting aspects of acetyl-CoA metabolism for the discovery of anti-cancer therapeutics.
We will test the feasibility of targeting a particular non-essential metabolic enzyme for the treatment of certain cancers. We hope these studies will provide novel insights into the mechanisms of cell growth control and contribute towards our understanding of metabolic strategies utilized by cancer cells to support proliferation.
|Ye, Cunqi; Tu, Benjamin P (2018) Sink into the Epigenome: Histones as Repositories That Influence Cellular Metabolism. Trends Endocrinol Metab 29:626-637|
|Huang, Zhiguang; Zhang, Menglu; Plec, Abigail A et al. (2018) ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. Proc Natl Acad Sci U S A 115:E9499-E9506|
|Walsh, Christopher T; Tu, Benjamin P; Tang, Yi (2018) Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism. Chem Rev 118:1460-1494|
|Dutchak, Paul A; Estill-Terpack, Sandi J; Plec, Abigail A et al. (2018) Loss of a Negative Regulator of mTORC1 Induces Aerobic Glycolysis and Altered Fiber Composition in Skeletal Muscle. Cell Rep 23:1907-1914|
|Chen, Jun; Sutter, Benjamin M; Shi, Lei et al. (2017) GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle. Nat Chem Biol 13:1179-1186|
|Dutchak, Paul A; Laxman, Sunil; Estill, Sandi Jo et al. (2015) Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2. Cell Rep 12:371-9|
|Huang, Zhiguang; Cai, Ling; Tu, Benjamin P (2015) Dietary control of chromatin. Curr Opin Cell Biol 34:69-74|
|Shi, Lei; Tu, Benjamin P (2015) Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 33:125-31|
|Comerford, Sarah A; Huang, Zhiguang; Du, Xinlin et al. (2014) Acetate dependence of tumors. Cell 159:1591-602|