Initially, our investigations focused on understanding the chemical biology and signaling properties of the free radical nitric oxide (•NO). Since its initial discovery as “endothelium-derived relaxing factor” in the 1980s, the understanding of •NO in biological systems has become vastly more complex. It is now known to be involved in numerous physiological functions ranging from smooth muscle relaxation and immune defenses to antioxidant activity and neuronal transmission. In addition to its many physiologic functions, •NO signaling is central to the etiology and progression of countless chronic diseases including cancer.
More specifically, the overarching goal of my research program is to elucidate novel biochemical and signaling properties of •NO and explain their contributions to the pathophysiology of cancer. Although there are numerous and well-studied means of •NO signaling, our findings have uncovered a novel mechanism of •NO signaling by revealing that the interactions of •NO with cellular iron pools can have dramatic effects on cell biology. Our research examines the cross-talk between •NO and iron signaling within the cell in an effort to elucidate mechanisms that underlie phenotypic outcomes.
Identification of •NO as an endogenously produced epigenetic regulatory molecule is the most significant finding to emerge from our studies. Post-translational modifications of histone lysine residues are an important epigenetic regulator of chromatin structure and gene transcription. Recently completed studies by our group revealed 3 novel and distinct mechanisms whereby •NO can affect post-translational histone modifications: direct inhibition of histone demethylase activity, reduction in iron cofactor availability, and changes in the expression of histone modifying enzymes. These results have the potential to fundamentally change the way we view this diatomic radical. Since evidence is continually emerging that demonstrates •NO is an important regulator in numerous tumor types, and iron is ubiquitous, our research is helping establish a coherent biochemical link between •NO, iron, epigenetic modifications, and tumor pathophysiology.
My current program, funded by R01 GM094175, focuses on three main areas that will expand our understanding of •NO chemical biology and cancer etiology:
Mechanisms of epigenetic regulation by •NO (DNA and Histone)
The reaction of •NO with iron and the consequences of dinitrosyliron complex formation
The relationship between hypoxia and •NO-driven tumor cell behavior