USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance

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, Jeongwu Lee

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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.

Original languageEnglish
Pages (from-to)37-47
Number of pages11
JournalNeuro-Oncology
Volume18
Issue number1
DOIs
StatePublished - 1 Jan 2016

Keywords

  • deubiquitination
  • glioblastoma stem cells
  • targeted therapy.

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