TY - JOUR
T1 - IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma
AU - Kofuji, Satoshi
AU - Hirayama, Akiyoshi
AU - Eberhardt, Alexander Otto
AU - Kawaguchi, Risa
AU - Sugiura, Yuki
AU - Sampetrean, Oltea
AU - Ikeda, Yoshiki
AU - Warren, Mikako
AU - Sakamoto, Naoya
AU - Kitahara, Shuji
AU - Yoshino, Hirofumi
AU - Yamashita, Daisuke
AU - Sumita, Kazutaka
AU - Wolfe, Kara
AU - Lange, Lisa
AU - Ikeda, Satsuki
AU - Shimada, Hiroko
AU - Minami, Noriaki
AU - Malhotra, Akshiv
AU - Morioka, Shin
AU - Ban, Yuki
AU - Asano, Maya
AU - Flanary, Victoria L.
AU - Ramkissoon, Annmarie
AU - Chow, Lionel M.L.
AU - Kiyokawa, Juri
AU - Mashimo, Tomoyuki
AU - Lucey, Greg
AU - Mareninov, Sergey
AU - Ozawa, Tatsuya
AU - Onishi, Nobuyuki
AU - Okumura, Koichi
AU - Terakawa, Jumpei
AU - Daikoku, Takiko
AU - Wise-Draper, Trisha
AU - Majd, Nazanin
AU - Kofuji, Kaori
AU - Sasaki, Mika
AU - Mori, Masaru
AU - Kanemura, Yonehiro
AU - Smith, Eric P.
AU - Anastasiou, Dimitrios
AU - Wakimoto, Hiroaki
AU - Holland, Eric C.
AU - Yong, William H.
AU - Horbinski, Craig
AU - Nakano, Ichiro
AU - DeBerardinis, Ralph J.
AU - Bachoo, Robert M.
AU - Mischel, Paul S.
AU - Yasui, Wataru
AU - Suematsu, Makoto
AU - Saya, Hideyuki
AU - Soga, Tomoyoshi
AU - Grummt, Ingrid
AU - Bierhoff, Holger
AU - Sasaki, Atsuo T.
N1 - Funding Information:
We thank the members of the Sasaki Lab, C. Mercer, D. Plas, T. Cunnigham, R. Hatakeyama, K. Ito, A. Kawakami, K. Kono, T. Nakamura, K. Sasaki, R. Kamata, Y. Hirota, T. Senda, K. Takeuchi, Y. Zheng, K. Hazeki, K. Nigorikawa and the Izayoi Society for feedback. We thank E. Dobbs for excellent editing. S. Kofuji is supported, in part, by Home for Innovative Researchers and Academic Knowledge Users (HIRAKU), JSPS KAKENHI grant number JP18K07233 and the Kanae Foundation. R.K. is supported by Grant-in-Aid for JSPS Fellows Grant Number JP17J01882. H.Y. was supported by the Uehara Memorial Foundation. K.S. was supported, in part, by the American Association of Neurological Surgeons. Work in the laboratory of D.A. was funded by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust (FC001033). R.J.D. is supported by grants from the NIH (R35CA220449). The MS imaging infrastructure was supported by the JST ERATO Suematsu Gas Biology Project (M. Suematsu, to March 2015). H.B. was supported by the Thuringian state programme ProExzellenz (RegenerAging—FSU-I-03/14) of the Thuringian Ministry for Research. The work is supported in part by a UC College of Medicine Research Innovation grant, an MTP UC-Brain Tumor Center grant, a MERF grant, a Marlene Harris Ride Cincinnati grant, an ABTA Discovery grant, a B*Cured research grant, an Ohio Cancer Research grant, R21NS100077 and R01NS089815 (A.T.S.).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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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U2 - 10.1038/s41556-019-0363-9
DO - 10.1038/s41556-019-0363-9
M3 - Article
C2 - 31371825
AN - SCOPUS:85066937054
SN - 1465-7392
VL - 21
SP - 1003
EP - 1014
JO - Nature cell biology
JF - Nature cell biology
IS - 8
ER -