1. Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.
- Author
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Hong JH, Kang S, Sa JK, Park G, Oh YT, Kim TH, Yin J, Kim SS, D'Angelo F, Koo H, You Y, Park S, Kwon HJ, Kim CI, Ryu H, Lin W, Park EJ, Kim YJ, Park MJ, Kim H, Kim MS, Chung S, Park CK, Park SH, Kang YH, Kim JH, Saya H, Nakano I, Gwak HS, Yoo H, Lee J, Hur EM, Shi B, Nam DH, Iavarone A, Lee SH, and Park JB
- Subjects
- Animals, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Inhibitor of Differentiation Protein 1 metabolism, Inhibitor of Differentiation Proteins metabolism, Mice, Inbred BALB C, Myelin Sheath pathology, Ubiquitin-Specific Proteases metabolism, Mice, Brain Neoplasms metabolism, Brain Neoplasms pathology, Glioblastoma metabolism, Glioblastoma pathology, Myelin Sheath metabolism, Nogo Receptor 1 metabolism
- Abstract
As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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