• Jin-Ku Lee, Nakho Chang, Yeup Yoon, Heekyoung Yang, Heejin Cho, Eunhee Kim, Yongjae Shin, Wonyoung Kang, Young Taek Oh, Gyeong In Mun, Kyeung Min Joo, Do-Hyun Nam, and Jeongwu Lee.
• Department of Neurosurgery, Samsung Medical Center and Samsung Biomedical Research Institute, Seoul, Korea (J.-K.L., Y.Y., H.Y., W.K., D.-H.N.); Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, Korea (N.C., H.C., Y.T.O., Y.Y., D.-H.N.); Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea (K.M.J.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio (E.K., Y.S., G.I.M., J.L.).
• Neuro-oncology. 2016 Jan 1; 18 (1): 37-47.

BackgroundClinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed.MethodsWe determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells.ResultsUSP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice.ConclusionUSP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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