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ALKBH5-mediated m6A-demethylation of USP1 regulated T-cell acute lymphoblastic leukemia cell glucocorticoid resistance by Aurora B
Molecular Carcinogenesis ( IF 4.6 ) Pub Date : 2021-06-25 , DOI: 10.1002/mc.23330
Hongtao Gong 1 , Liu Liu 2 , Lina Cui 3 , Hongyan Ma 1 , Liyun Shen 1
Affiliation  

Recent studies evidence that ubiquitin-specific proteases (USPs) are associated with the occurrence and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL). N6-methyladenosine (m6A) demethylase AlkB homolog 5 (ALKBH5) exerts a carcinogenic effect in human cancers and improves the mRNA stability of USPs. Whether ubiquitin-specific protease 1 (USP1) controls chemoresistance of T-ALL is unknown. Our study demonstrated that USP1 expression was upregulated in glucocorticoid (GC)-resistant T-ALL patients and cells (CEM-C1). High expression of USP1 was correlated to the poor prognosis in T-ALL patients. Silencing USP1 increased CEM-C1 cell sensitivity to dexamethasone (Dex), reduced cell invasion, promoted cell apoptosis, and ameliorated glucocorticoid receptor (GR) expression. USP1 mediated T-ALL chemoresistance by interacting with and deubiquitination of Aurora B. Overexpression of USP1 reversed the amelioration effect of Aurora B inhibitor on CEM-C1 cell resistance to Dex. Mechanistically, ALKBH5 enhanced USP1 expression by reducing m6A level and mRNA stability in USP1 mRNA transcript. Downregulation of ALKBH5 reduced the levels of USP1 and Aurora B, facilitated CEM-C1 cell sensitivity to Dex, apoptosis, and GR expression, suppressed cell invasion. However, overexpression of USP1 reversed all the effects of ALKBH5 on CEM-C1 cells. In vivo results showed that tail vein injection of sh-USP1 resulted in a significant prolongation of mouse survival, suppressed tumor growth, maintained the normal weight of mice, reduced USP1 expression and facilitated GR expression. In conclusion, inhibition of ALKBH5-mediated m6A modification decreased USP1 expression and downregulation of USP1 ameliorated GC resistance of T-ALL through suppressing Aurora B expression and elevating GR level.

中文翻译:

ALKBH5 介导的 USP1 的 m6A 去甲基化调节 T 细胞急性淋巴细胞白血病细胞对 Aurora B 的糖皮质激素抵抗

最近的研究表明,泛素特异性蛋白酶 (USP) 与 T 细胞急性淋巴细胞白血病 (T-ALL) 的发生和耐药性有关。N 6-甲基腺苷 (m6A) 脱甲基酶 AlkB 同源物 5 (ALKBH5) 在人类癌症中发挥致癌作用并提高 USP 的 mRNA 稳定性。泛素特异性蛋白酶 1 (USP1) 是否控制 T-ALL 的化学抗性尚不清楚。我们的研究表明 USP1 表达在糖皮质激素 (GC) 抗性 T-ALL 患者和细胞 (CEM-C1) 中上调。USP1 的高表达与 T-ALL 患者的不良预后相关。沉默 USP1 会增加 CEM-C1 细胞对地塞米松 (Dex) 的敏感性,减少细胞侵袭,促进细胞凋亡,并改善糖皮质激素受体 (GR) 的表达。USP1 通过与 Aurora B 相互作用和去泛素化介导 T-ALL 化学抗性。 USP1 的过表达逆转了 Aurora B 抑制剂对 CEM-C1 细胞对 Dex 抗性的改善作用。从机制上讲,ALKBH5 通过降低 USP1 mRNA 转录物中的 m6A 水平和 mRNA 稳定性来增强 USP1 表达。ALKBH5 的下调降低了 USP1 和 Aurora B 的水平,促进了 CEM-C1 细胞对 Dex、细胞凋亡和 GR 表达的敏感性,抑制了细胞侵袭。然而,USP1 的过表达逆转了 ALKBH5 对 CEM-C1 细胞的所有影响。体内结果表明,尾静脉注射sh-USP1可显着延长小鼠存活时间,抑制肿瘤生长,维持小鼠正常体重,降低USP1表达并促进GR表达。总之,抑制 ALKBH5 介导的 m6A 修饰降低了 USP1 表达,下调 USP1 通过抑制 Aurora B 表达和提高 GR 水平改善了 T-ALL 的 GC 抗性。
更新日期:2021-08-10
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