Lisa Heppler, Brigham Young University
Chemistry and Biochemistry
Solid breast tumors contain heterogenous microenvironments where tumor cells are often exposed to metabolic stress (e.g., hypoxia due to poor blood supply). Such environments select for tumor cells that can adapt metabolically to survive, while other cells fail to adapt and undergo cell death. The survival of cells through periods of hypoxia can promote chemoresistance and metastasis (1). Thus, it is critical that we develop therapeutic strategies to enhance metabolic-stress-induced tumor cell death. One promising strategy is the modulation of lysine acetylation pathways by HDAC inhibitors that potently pro- mote cell death in response to various stimuli, including hypoxia/glucose withdrawal. Given the relatively non-specific nature of chemical HDAC inhibitors, the precise acetylation-regulating enzymes and pathways that govern cell death in these settings have yet to be fully elucidated. Our goal is to identify the cellular factors that link acetylation to cell death in response to hypoxia and other metabolic stresses, with the hope that such factors could be exploited therapeutically in cancer. Previous studies have implicated protein lysine acetylation in the coordination of cellular metabolism to the available nutrient supply (2). In line with this idea, our preliminary data suggest that lysine acetylation pathways dictate whether breast tumor cells survive (through metabolic adaptation) or die in response to hypoxia and glucose deprivation. Moreover, we have observed that general increases in protein lysine acetylation precede the activation of pro-apoptotic caspases in response to these stresses. In addition, our proteomics efforts have shown that breast tumors that are sensitive to hypoxia/glucose withdrawal exhibit significant increases in acetylation across the proteome, whereas resistant cells show very little change. Together, our data suggest that lysine acetylation pathways play a role in metabolic adaption and survival under conditions of hypoxia/glucose withdrawal. We are currently using an RNAi approach to target all known deacetylases, acetyl-transferases, and metabolic enzymes that modulate acetylation (e.g., acetyl-CoA synthetase) in order to identify the specific acetylation-regulating factors that govern tumor cell susceptibility to metabolic stress.