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Nat Cell Biol. 2019 Aug;21(8):1003-1014. doi: 10.1038/s41556-019-0363-9. Epub 2019 Aug 1.

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

Author information

1
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
2
Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
3
Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
4
Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany.
5
Leibniz-Institute on Aging-Fritz Lipmann Institute, Jena, Germany.
6
Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
7
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
8
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
9
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
10
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
11
Department of Anatomy and Developmental Biology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
12
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
13
Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
14
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
15
Department of Internal Medicine; Harold C. Simmons Comprehensive Cancer Center; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
16
Division of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
17
Division of Human Biology, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
18
Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
19
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
20
Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan.
21
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
22
Cancer Metabolism Laboratory, The Francis Crick Institute, London, UK.
23
Department of Pathology, University of Kentucky College of Medicine, Lexington, KY, USA.
24
Departments of Pathology and Neurosurgery, Northwestern University, Chicago, IL, USA.
25
Howard Hughes Medical Institute; Children's Medical Center Research Institute; Department of Pediatrics and Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
26
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
27
Ludwig Institute for Cancer Research; Department of Pathology; Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA.
28
AMED-CREST, AMED, Tokyo, Japan.
29
Division of Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
30
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. atsuo.sasaki@uc.edu.
31
Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan. atsuo.sasaki@uc.edu.
32
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. atsuo.sasaki@uc.edu.
33
Department of Neurosurgery, Brain Tumor Center at UC Gardner Neuroscience Institute, Cincinnati, OH, USA. atsuo.sasaki@uc.edu.

Abstract

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

PMID:
31371825
PMCID:
PMC6686884
[Available on 2020-02-01]
DOI:
10.1038/s41556-019-0363-9

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