IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma
IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma
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DOI：
10.1038/s41556-019-0363-9
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发表时间：
2019-08-01
影响因子：
21.3
通讯作者：
Sasaki, Atsuo T.
中科院分区：
文献类型：
--
作者：
Kofuji, Satoshi;Hirayama, Akiyoshi;Sasaki, Atsuo T.
在许多癌症中，高增殖率与rRNA和tRNA水平升高以及核仁肥大相关。然而，核仁转录增加和肿瘤发生的潜在机制仅知之甚少。在这里，我们表明，IMP脱氢酶-2（IMPDH 2），从头鸟嘌呤核苷酸生物合成的限速酶，在高致死性脑癌胶质母细胞瘤中过表达。这导致rRNA和tRNA合成增加，核仁GTP结合蛋白nucleostemin的稳定化，以及增大的畸形核仁。胶质母细胞瘤中IMPDH 2的药理学或遗传失活逆转了这些作用并抑制细胞增殖，而未转化的胶质细胞不受类似IMPDH 2扰动的影响。IMPDH 2活性的损害触发胶质母细胞瘤细胞的核仁应激和生长停滞，即使在功能性p53不存在的情况下。我们的研究结果表明，IMPDH 2的上调是发生异常核仁功能和胶质母细胞瘤合成代谢过程增加的先决条件，这构成了胶质瘤发生的主要事件。
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.