nihms-1532281.pdf (2.88 MB)
IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.
journal contributionposted on 2020-10-28, 14:02 authored by Satoshi Kofuji, Akiyoshi Hirayama, Alexander Otto Eberhardt, Risa Kawaguchi, Yuki Sugiura, Oltea Sampetrean, Yoshiki Ikeda, Mikako Warren, Naoya Sakamoto, Shuji Kitahara, Hirofumi Yoshino, Daisuke Yamashita, Kazutaka Sumita, Kara Wolfe, Lisa Lange, Satsuki Ikeda, Hiroko Shimada, Noriaki Minami, Akshiv Malhotra, Shin Morioka, Yuki Ban, Maya Asano, Victoria L Flanary, Annmarie Ramkissoon, Lionel ML Chow, Juri Kiyokawa, Tomoyuki Mashimo, Greg Lucey, Sergey Mareninov, Tatsuya Ozawa, Nobuyuki Onishi, Koichi Okumura, Jumpei Terakawa, Takiko Daikoku, Trisha Wise-Draper, Nazanin Majd, Kaori Kofuji, Mika Sasaki, Masaru Mori, Yonehiro Kanemura, Eric P Smith, Dimitrios Anastasiou, Hiroaki Wakimoto, Eric C Holland, William H Yong, Craig Horbinski, Ichiro Nakano, Ralph J DeBerardinis, Robert M Bachoo, Paul S Mischel, Wataru Yasui, Makoto Suematsu, Hideyuki Saya, Tomoyoshi Soga, Ingrid Grummt, Holger Bierhoff, Atsuo T Sasaki
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.