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

Nature Cell Biology
Satoshi KofujiAtsuo T Sasaki

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.

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Citations

Sep 25, 2019·Cancers·Marcella CamiciMaria Grazia Tozzi
Sep 14, 2019·Cancers·Rand NaffoujeAtsuo T Sasaki
Apr 21, 2020·Biochemical Society Transactions·Davide M FerrarisMenico Rizzi
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Aug 12, 2020·Phytotherapy Research : PTR·Wanyan WangJin Huang
Apr 10, 2020·JCI Insight·Alexander J ValvezanBrendan D Manning
Jul 24, 2020·Journal of Biochemistry·Satoshi Kofuji, Atsuo T Sasaki
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Jun 15, 2019·Biochemical and Biophysical Research Communications·Kara WolfeAtsuo T Sasaki
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Jul 11, 2021·Journal of Biochemistry·Yoshiki IkedaAtsuo T Sasaki

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Datasets Mentioned

BETA
GSE45874

Methods Mentioned

BETA
xenograft
electrophoresis
xenografts
PCR
ChIP
immunoprecipitation
transmission electron microscopy
Assay

Software Mentioned

GraphPad
R package
MOIRAI
ImageJ
prcomp R package
R
GraphPad Prism
Agilent MassHunter
FlexImaging
topGO

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