USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance
USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance
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DOI：
10.1093/neuonc/nov091
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发表时间：
2016-01-01
期刊：
影响因子：
15.9
通讯作者：
Lee, Jeongwu
中科院分区：
文献类型：
--
作者：
Lee, Jin-Ku;Chang, Nakho;Lee, Jeongwu
来自针对胶质母细胞瘤（GBM）的标准疗法的临床益处部分地由于GBM的固有放射性和化学抗性以及GBM干细胞样细胞（GSC）的低效靶向而受到限制。我们通过转录组分析确定了泛素化特异性蛋白酶（ubiquitination-specific proteases，USPs）的表达水平，发现USP 1在GBM中高表达。利用患者GBM来源的原代肿瘤细胞，我们通过shRNA介导的敲除或其特异性抑制剂pimozide抑制USP 1，并评估其对肿瘤细胞干细胞标志物表达、增殖和克隆形成生长的影响。USP 1正调控ID 1和CHEK 1的蛋白质稳定性，这是DNA损伤反应和干细胞维持的关键调节因子。通过RNA干扰靶向USP 1或用化学USP 1抑制剂处理减弱了GSC的克隆生长和存活，并增强了GBM细胞的放射敏感性。最后，单独或联合使用USP 1抑制剂和放射治疗可显著延长荷瘤小鼠的生存期。USP 1介导的蛋白稳定性可促进GSC的维持和治疗抗性，从而为USP 1抑制剂作为GBM的潜在治疗方法提供了理论基础。
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.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.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.USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.