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

• Published in: Nature cell biology Vol. 21; no. 8; pp. 1003 - 1014
• Main Authors: Kofuji, Satoshi, Hirayama, Akiyoshi, Eberhardt, Alexander Otto, Kawaguchi, Risa, Sugiura, Yuki, Sampetrean, Oltea, Ikeda, Yoshiki, Warren, Mikako, Sakamoto, Naoya, Kitahara, Shuji, Yoshino, Hirofumi, Yamashita, Daisuke, Sumita, Kazutaka, Wolfe, Kara, Lange, Lisa, Ikeda, Satsuki, Shimada, Hiroko, Minami, Noriaki, Malhotra, Akshiv, Morioka, Shin, Ban, Yuki, Asano, Maya, Flanary, Victoria L., Ramkissoon, Annmarie, Chow, Lionel M. L., Kiyokawa, Juri, Mashimo, Tomoyuki, Lucey, Greg, Mareninov, Sergey, Ozawa, Tatsuya, Onishi, Nobuyuki, Okumura, Koichi, Terakawa, Jumpei, Daikoku, Takiko, Wise-Draper, Trisha, Majd, Nazanin, Kofuji, Kaori, Sasaki, Mika, Mori, Masaru, Kanemura, Yonehiro, Smith, Eric P., Anastasiou, Dimitrios, Wakimoto, Hiroaki, Holland, Eric C., Yong, William H., Horbinski, Craig, Nakano, Ichiro, DeBerardinis, Ralph J., Bachoo, Robert M., Mischel, Paul S., Yasui, Wataru, Suematsu, Makoto, Saya, Hideyuki, Soga, Tomoyoshi, Grummt, Ingrid, Bierhoff, Holger, Sasaki, Atsuo T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2019; Nature Publishing Group
• Subjects: 13/51; 38/1; 38/39; 45/61; 59/5; 631/67; 631/67/2327; 631/80/386/1362; 82/58; 96/63; Biomedical and Life Sciences; Biosynthesis; Brain; Brain cancer; Cancer Research; Carcinogenesis - metabolism; Cell Biology; Cell Line, Tumor; Cell Nucleolus - metabolism; Cell proliferation; Cell Proliferation - physiology; Cell Transformation, Neoplastic - metabolism; Deactivation; Dehydrogenase; Dehydrogenases; Development and progression; Developmental Biology; Glioblastoma; Glioblastoma - metabolism; Glioblastoma cells; Glioblastoma multiforme; GTP-binding protein; Guanine; Health aspects; Humans; Hypertrophy; IMP dehydrogenase; IMP Dehydrogenase - genetics; IMP Dehydrogenase - metabolism; Inactivation; Life Sciences; Nucleoli; Nucleolus organizer region; Nucleostemin; Nucleotides; Oxidoreductases; p53 Protein; Physiological aspects; RNA, Ribosomal - metabolism; rRNA; Stem Cells; Transcription; tRNA; Tumorigenesis; Japan
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-019-0363-9

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.
Kofuji et al. demonstrate that upregulation of IMPDH2 promotes nucleostemin stabilization and nucleoli malformation, and its inactivation induces growth arrest in glioblastoma.