title: 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.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Amit D
authors.initials: AD
authors.lastname: Gujar
authors.affiliation: Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32605.
authors.forename: Son
authors.initials: S
authors.lastname: Le
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Diane D
authors.initials: DD
authors.lastname: Mao
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110.|Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: David Y A
authors.initials: DY
authors.lastname: Dadey
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Alice
authors.initials: A
authors.lastname: Turski
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Diane
authors.initials: D
authors.lastname: Aum
authors.affiliation: Division of Biostatistics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Sonika
authors.initials: S
authors.lastname: Dahiya
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Liya
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Rich
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.|Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110.|Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.|Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Hiroko
authors.identifier: 0000-0001-6548-0920
authors.initials: H
authors.lastname: Yano
authors.affiliation: Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32605.
authors.forename: David D
authors.initials: DD
authors.lastname: Tran
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110; kima@wudosis.wustl.edu.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.|Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D009154:Mutation; D009243:NAD / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics*; D034622:RNA Interference; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: NAD+; NAMPT; glioblastoma; radiation resistance; self-renewal