Jin-Ku Lee1, Nakho Chang1, Yeup Yoon1, Heekyoung Yang1, Heejin Cho1, Eunhee Kim1, Yongjae Shin1, Wonyoung Kang1, Young Taek Oh1, Gyeong In Mun1, Kyeung Min Joo1, Do-Hyun Nam1, Jeongwu Lee1. 1. 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.).
Abstract
BACKGROUND: Clinical 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. METHODS: We 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. RESULTS: USP1 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. CONCLUSION: USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.
BACKGROUND: Clinical 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. METHODS: We 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. RESULTS:USP1 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. CONCLUSION:USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.
Authors: Sebastian M B Nijman; Tony T Huang; Annette M G Dirac; Thijn R Brummelkamp; Ron M Kerkhoven; Alan D D'Andrea; René Bernards Journal: Mol Cell Date: 2005-02-04 Impact factor: 17.970
Authors: Sebastian M B Nijman; Mark P A Luna-Vargas; Arno Velds; Thijn R Brummelkamp; Annette M G Dirac; Titia K Sixma; René Bernards Journal: Cell Date: 2005-12-02 Impact factor: 41.582
Authors: Shideng Bao; Qiulian Wu; Roger E McLendon; Yueling Hao; Qing Shi; Anita B Hjelmeland; Mark W Dewhirst; Darell D Bigner; Jeremy N Rich Journal: Nature Date: 2006-10-18 Impact factor: 49.962
Authors: Jeongwu Lee; Svetlana Kotliarova; Yuri Kotliarov; Aiguo Li; Qin Su; Nicholas M Donin; Sandra Pastorino; Benjamin W Purow; Neil Christopher; Wei Zhang; John K Park; Howard A Fine Journal: Cancer Cell Date: 2006-05 Impact factor: 31.743
Authors: Arkady Celeste; Oscar Fernandez-Capetillo; Michael J Kruhlak; Duane R Pilch; David W Staudt; Alicia Lee; Robert F Bonner; William M Bonner; André Nussenzweig Journal: Nat Cell Biol Date: 2003-07 Impact factor: 28.824
Authors: Sheila K Singh; Cynthia Hawkins; Ian D Clarke; Jeremy A Squire; Jane Bayani; Takuichiro Hide; R Mark Henkelman; Michael D Cusimano; Peter B Dirks Journal: Nature Date: 2004-11-18 Impact factor: 49.962
Authors: Urszula L McClurg; Nay C T H Chit; Mahsa Azizyan; Joanne Edwards; Arash Nabbi; Karl T Riabowol; Sirintra Nakjang; Stuart R McCracken; Craig N Robson Journal: Oncogene Date: 2018-05-14 Impact factor: 9.867
Authors: Peter J Cook; Rozario Thomas; Philip J Kingsley; Fumiko Shimizu; David C Montrose; Lawrence J Marnett; Viviane S Tabar; Andrew J Dannenberg; Robert Benezra Journal: Neuro Oncol Date: 2016-03-28 Impact factor: 12.300