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

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.

• Authors: 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 M Rich, Jeffrey Milbrandt, Dennis E Hallahan, Hiroko Yano, David D Tran, Albert H Kim
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 51 Pg. E8247-E8256 (12 20 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27930300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokines
• NAD
• Nicotinamide Phosphoribosyltransferase
• nicotinamide phosphoribosyltransferase, human

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Brain (pathology)
• Brain Neoplasms (metabolism, radiotherapy)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation
• Cytokines (genetics)
• Gene Expression Regulation, Neoplastic
• Glioblastoma (metabolism, radiotherapy)
• Humans
• Mice
• Mutation
• NAD (biosynthesis)
• Neoplasm Transplantation
• Nicotinamide Phosphoribosyltransferase (genetics)
• RNA Interference
• Radiation Tolerance
• Signal Transduction (drug effects)
• Stem Cells (cytology)
• Transcription, Genetic