南方医科大学学报2024，Vol.44Issue(8)：1620-1630,11.DOI:10.12122/j.issn.1673-4254.2024.08.22
ORY-1001靶向赖氨酸特异性去甲基化酶1下调胶质母细胞瘤Notch/HES1通路的表达并发挥抗肿瘤作用
ORY-1001 inhibits glioblastoma cell growth by downregulating the Notch/HES1 pathway via suppressing lysine-specific demethylase 1 expression
摘要
Abstract
Objective To explore the inhibitory effect ORY-1001,a lysine-specific histone demethylase 1(LSD1)inhibitor,on growth of glioblastoma(GBM)and the underlying mechanism.Methods We analyzed LSD1 expressions in GBM and normal brain tissues based on data from TCGA and HPA databases.Female BALB/c mouse models bearing xenografts derived from U87 cells or cells with lentivirus-mediated LSD1 silencing or Notch overexpression were treated with saline or 400 µg/kg ORY-1001 by gavage every 7 days,and GBM formation and survival time of the mice were recorded.The effect of ORY-1001 on GBM cell viability was assessed,and its effect on LSD1 expression was analyzed with Western blotting.The genes and pathways associated with LSD1 were analyzed using bioinformatics methods.Western blotting and qRT-PCR were used to detect Notch/HES1 pathway expression after LSD1 silencing and ORY-1001 treatment.The impact of ORY-1001 on viability of U87 cells with Notch1 silencing or overexpression was assessed,and the regulatory effects of ORY-1001 on Notch/HES1 pathway were analyzed using chromatin immunoprecipitation assay.Results A high expression of LSD1 in GBM was negatively correlated with patient survival(P<0.001).ORY-1001 and LSD1 silencing obviously reduced tumor burden and prolonged the survival time of GBM-bearing mice.ORY-1001 treatment significantly inhibited the viability and dose-dependently decreased LSD1 expression in GBM cells,and such inhibitory effect of ORY-1001 was attenuated by LSD1 silencing.The Notch pathway enriched the differential genes related to LSD1,and Notch/HES1 pathway expression was significantly down-regulated after LSD1 silencing and ORY-1001 treatment.Notch1 overexpression significantly attenuated the anti-tumor effect of ORY-1001 on GBM.Mechanistically,ORY-1001 disrupted the interaction between LSD1 and the Notch pathway target genes including Notch3,HES1 and CR2.Conclusion ORY-1001 down-regulates the Notch/HES1 pathway by inhibiting LSD1 expression to suppress the growth of GBM in mice.关键词
赖氨酸特异性去甲基化酶1/生信分析/胶质母细胞瘤/Notch/HES1通路/癌症治疗Key words
Lysine-specific histone demethylase 1/bioinformatics analysis/glioblastoma/Notch/HES1 pathway/cancer treatment引用本文复制引用
杨红丽,向亚运,谭婷婷,雷阳..ORY-1001靶向赖氨酸特异性去甲基化酶1下调胶质母细胞瘤Notch/HES1通路的表达并发挥抗肿瘤作用[J].南方医科大学学报,2024,44(8):1620-1630,11.基金项目
重庆市自然科学基金(cstc2020jcyj-msxmX0323) （cstc2020jcyj-msxmX0323）
