SUN-LB053 Metabolic Interaction of SAH and SAM in hPheo1 Cells

Abstract

Pheochromocytomas/paragangliomas (PCC/PGLs) are neuroendocrine tumors, that arise either from the adrenal medulla or sympathetic/parasympathetic chain ganglia. The PCC/PGL tumors that have inactivating mutations in the succinate dehydrogenase type B (SDHB) complex are associated with malignant and metastatic behavior. As a result of decreased conversion of succinate to fumarate due to a SDHB mutation, succinate acquires oncometabolite properties and modulates histone demethylases. It has been shown that many epigenetic changes alter the expression of metabolic enzymes involved in glycolysis and glutaminolysis. The availability of one-carbon units for DNA methylation is heavily dependent on the presence of serine and glycine, either from de novo synthesis or from cellular uptake. Using a global metabolic approach in human progenitor cells derived from a pheochromocytoma (hPheo1) cells, we now show that hPheo1 SDHB knock-out cells accumulate succinate and subsequently deregulated one carbon cycle. Importantly, we identified a "hypermethylated cell" state as evidenced by an accumulation of S-adenosyl-homocysteine (SAH) and a further reduction of S-adenosylmethionine (SAM) in the hPheo1 SDHB knock out cells compared to the wild-type cells. We also observed a dramatic reduction in glycine and serine, as well as lack of folic acid in the hPheo1 SDHB knock-out cells. This suggests that the hypermethylated state results in a depletion of these metabolites which are involved in the one-carbon cycle. Our results in hPheo1 cells further confirm the key role of increased methylation that is associated with SDHB mutation. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.