Defining the Role of DLST in MYCN-Driven Neuroblastoma
Background
Aberrant MYCN activity is found in ~30% of patients with neuroblastoma and is associated with highly aggressive tumors and poor prognosis. Our preliminary work has demonstrated that dihydrolipoamide S-succinyltransferase (DLST) plays an important role in MYCN-driven neuroblastoma pathogenesis. DLST is the E2 component of the enzymatic complex–ketoglutarate dehydrogenase complex (KGDHC), which catalyzes an irreversible step in the tricarboxylic acid (TCA) cycle. Beyond its classical role, DLST is a component of the lysine degradation pathway and was recently shown to regulate gene expression through succinylation of lysine residues on histones. Utilizing human neuroblastoma cell lines, we have demonstrated that MYCN-amplified cells are sensitive to DLST inhibition as demonstrated by slowed cell growth and the induction of apoptosis. We hypothesize that the nuclear fraction of DLST contributes to neuroblastoma pathogenesis.
Project Goal
Goal 1: Determine the subcellular localization of DLST in human and zebrafish MYCN-driven neuroblastoma. Utilizing a combination of human MYCN-amplified neuroblastoma cell lines (Kelly and BE2C) and zebrafish MYCN-driven tumor cells, we will determine the subcellular localization of DLST in MYCN-driven neuroblastoma cells by immunofluorescence. Goal 2: Determine if nuclear DLST contributes to neuroblastoma pathogenesis. Previously, we have shown that MYCN-amplified human neuroblastoma cell lines are sensitive to DLST inhibition via shRNA knockdown and this growth defect can be genetically rescued by overexpression of DLST.
Mentored by Dr. Nicole Anderson
University of Pennsylvania, Philadelphia, PA
