title: Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2.
abstract: Deamidation of glutamine to glutamate by glutaminase 1 (GLS1, also called GLS) and GLS2 is an essential step in both glutaminolysis and glutathione (GSH) biosynthesis. However, mechanisms whereby cancer cells regulate glutamine catabolism remains largely unknown. We report here that N-Myc, an essential Myc family member, promotes conversion of glutamine to glutamate in MYCN-amplified neuroblastoma cells by directly activating GLS2, but not GLS1, transcription. Abrogation of GLS2 function profoundly inhibited glutaminolysis, which resulted in feedback inhibition of aerobic glycolysis likely due to thioredoxin-interacting protein (TXNIP) activation, dramatically decreasing cell proliferation and survival in vitro and in vivo. Moreover, elevated GLS2 expression is significantly elevated in MYCN-amplified neuroblastomas in comparison with non-amplified ones, correlating with unfavorable patient survival. In aggregate, these results reveal a novel mechanism deciphering context-dependent regulation of metabolic heterogeneities, uncovering a previously unsuspected link between Myc, GLS2 and tumor metabolism.
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Daibiao
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Hubei University of Science & Technology, Xianning 437100, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ren
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Hexiu
authors.initials: H
authors.lastname: Su
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yue
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Xiu
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.|Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors.forename: Hudan
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.|Medical Research Institute, Wuhan University, Wuhan 430071, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Qing
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004789:Enzyme Activation; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D006868:Hydrolysis; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D005973:Glutamine; C586504:GLS2 protein, human; D005972:Glutaminase
keywords: N-Myc; cancer metabolism; glutaminase 2; glutamine; neuroblastoma