201901Yamamoto

研究発表を行った学会；The 2nd JSPS-NUS Joint Symposium
2018年 1月18日（熊本）
タイトル； Detoxification of N6-isopentenyladenosine by Cdk5rap1 controls the cell fate of glioma initiating cells.
発表者；山本　隆広氏
（熊本大学　大学院生命科学研究部　分子生理学分野　脳神経外科学分野）
要旨；
Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor. Glioma initiating cells (GIC), which exhibit stem cell-like features, are considered as the origin of GBM. Previous studies have shown that mitochondria-mediated metabolism is critical to the maintenance of GIC, but the molecular mechanism remains unclearly. We have identified CDK5 Regulatory Subunit Associated Protein 1 (Cdk5rap1) as tRNA-modifying enzyme, which converts N6-isopentenyladenosine (i6A) to 2-methylthio-N6-isopentenyladenosine (ms2i6A) at position A37 of a subsets of mitochondrial tRNAs. Cdk5rap1-mediated ms2-modification is important for efficient mitochondrial protein translation as well as energy metabolism.
In the present study, we investigated the role of Cdk5rap1 in the maintenance of GIC and its relevance with GBM. The mRNA level of Cdk5rap1 was positively correlated with several stem markers, but was negatively correlated with overall survival of GBM patients. We established GIC lines from GBM patients in Kumamoto University. Knocking-down of Cdk5rap1 reduced cell viability and stemness of GIC. Surprisingly, the cytotoxic effect was independent of mitochondrial energy metabolism, but rather attributed to the nucleoside metabolism. Cdk5rap1-deficiency resulted in a decrease of ms2i6A and increased i6A content in GIC. Application of i6A, but not ms2i6A, markedly reduced cell viability and stemness of GIC. Thus, Cdk5rap1 is important for the maintenance of GIC by detoxificating i6A to ms2i6A.