An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Amit D. Gujar, Son Le, Diane D. Mao, David Y.A. Dadey, Alice Turski, Yo Sasaki, Diane Aum, Jingqin Luo, Sonika Dahiya, Liya Yuan, Keith Rich, Jeffrey Milbrandt, Dennis Hallahan, Hiroko Yano, David D. Tran, Albert Kim

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD+). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD+ synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD+ levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD+-dependent network. Accordingly, we demonstrate E2F2 is required for GSC self-renewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD+ metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.

Original languageEnglish
Pages (from-to)E8247-E8256
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number51
DOIs
StatePublished - Dec 20 2016

Keywords

  • Glioblastoma
  • NAD
  • NAMPT
  • Radiation resistance
  • Self-renewal

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