Understanding the epigenetic basis of human familial paraganglioma. Our laboratory is interested in understanding how defects in metabolism can promote tumorigenesis. Specifically, we study familial paraganglioma (PGL), a neuroendocrine cancer, as a model that exemplifies metabolic derangement. Familial PGL displays autosomal dominant inheritance and is due to loss of both copies of genes encoding subunits of succinate dehydrogenase (SDH), a tricarboxylic acid (TCA) cycle enzyme. Loss of SDH function is particularly interesting because it exemplifies the Warburg effect of aerobic glycolysis, a mysterious feature of many cancers. To date, there is no clear explanation for how loss of SDH function leads to tumor formation in neuroendocrine cells. Furthermore, there is no preclinical model to study this cancer. The long-term goal of this proposal is to understand how loss of function of SDH induces PGL in neuroendocrine cells. This knowledge will provide new approaches to PGL prevention and treatment. Our central hypothesis is that dioxygenase inhibition by succinate accumulation causes oncogenic epigenetic effects including activation of Hypoxia Inducible Factor (HIF), accumulation of histone methylation, and depletion of 5-hydroxymethyl-deoxycytosine (5hmdC). Our strategy is to develop three models to study succinate accumulation. These include (1) human familial PGL tumor histology specimens, (2) SDHB lentiviral knockdown human tissue culture cells, and (3) a mouse SDHC-/- cell line.
Aim 1 will examine the effects of SDH loss in PGL tumor specimens.
Aim 2 will determine effects of SDH knockdown in tissue culture cells and if these effects can be overcome by SDH gene replacement or increasing 2-ketoglutarate levels. Finally, Aim 3 will characterize the effects of SDH loss in a mouse SDHC-/- cell line.
Paragangliomas (PGLs) are neuroendocrine tumors that often progress to difficult malignant cancers, presenting with symptoms such as hypertension, palpitations, headaches, cranial nerve palsies, and tinnitus. It is bizarre that loss of function o succinate dehydrogenase, a TCA cycle enzyme that is highly conserved from bacteria to human, triggers tumorigenesis and not cellular death from ATP starvation. We hypothesized that succinate accumulation due to loss of SDH function inhibits 2- ketogluatarate-dependetn dioxygenase enzymes in PGL tumor cells. The knowledge gained from this research could provide new therapeutic approaches to paraganglioma treatment and prevention. More importantly, since metabolic derangement is a hallmark of many cancers, better understanding of the effect of metabolite imbalances on cell growth control is of broad significance to human health.
|Peters, Justin P; Her, Yeng F; Maher 3rd, L James (2015) Modeling dioxygenase enzyme kinetics in familial paraganglioma. Biol Open 4:1281-9|
|Badal, Sujan; Her, Yeng F; Maher 3rd, L James (2015) Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells. J Biol Chem 290:22287-97|
|Her, Yeng F; Nelson-Holte, Molly; Maher 3rd, Louis James (2015) Oxygen concentration controls epigenetic effects in models of familial paraganglioma. PLoS One 10:e0127471|
|Her, Yeng F; Maher 3rd, L James (2015) Succinate Dehydrogenase Loss in Familial Paraganglioma: Biochemistry, Genetics, and Epigenetics. Int J Endocrinol 2015:296167|