CSIG-20. IDENTIFICATION OF A NAMPT-E2F2-ID1 SIGNALING AXIS IN GLIOBLASTOMA

Abstract

Emerging evidence shows that nicotinamide adenine dinucleotide (NAD+)-dependent signaling plays a critical role in a variety of biological contexts including cancer. The rate-limiting enzyme of the mammalian NAD+ synthesis pathway, nicotinamide phosphoribosyltransferase (NAMPT), governs NAD+-dependent processes by catalyzing production of nicotinamide mononucleotide (NMN), a key NAD+ precursor. However, the role and molecular mechanisms of NAMPT in the biology of human glioblastoma have remained poorly understood. Here, we demonstrate that NAMPT is highly expressed in glioblastoma tumor specimens and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in glioblastoma tumors correlates with poor prognosis in patients. NAMPT inhibition using FK866 as well as RNA interference (RNAi) depleted NAD+ levels in GSCs and substantially decreased GSC self-renewal. Importantly, NAMPT knockdown diminished the in vivo tumorigenicity of GSCs and prolonged the survival of animals in an orthotopic xenograft model. Bioinformatic analysis of RNA-sequencing data derived from FK866-treated GSCs revealed E2F family transcription factor E2F2 as a potential hub of the NAD+-dependent transcriptome. Accordingly, E2F2 knockdown decreased the self-renewal capacity of GSCs. Downstream, we find that E2F2 directly controls the transcription of helix-loop-helix protein inhibitor of differentiation 1 (ID1), a known regulator of self-renewal. Finally, we show that NAMPT promotes radiation resistance of GSCs in culture, highlighting the potential therapeutic relevance of this pathway. The identification of a NAMPT-E2F2-ID1 signaling pathway, which regulates GSC maintenance, has ramifications for the development of novel therapeutic strategies for glioblastoma patients.