抑制USP53-ALKBH5轴促进m6A修饰的TERT RNA降解：胶质母细胞瘤的潜在治疗策略
USP53-ALKBH5 axis inhibition boosts m6A-modified TERT RNA degradation: A potential therapeutic strategy for glioblastoma.
摘要(中文译文)
胶质母细胞瘤（GBM）是最常见的恶性胶质瘤，复发率高且预后差。去泛素化酶泛素特异性肽酶53（USP53）已知可增强下游蛋白的稳定性，在不同肿瘤中表现出不同的功能。USP53在GBM进展中的功能尚不清楚。对GSE104267和GSE4290数据集的分析显示，USP53在GBM组织中显著上调，TCGA数据比较GBM（n=163）与正常脑组织（n=207）也证实了这一发现。在单因素和多因素Cox回归分析中，USP53被确定为GBM进展的独立危险因素（单因素，风险比（HR）=1.5357，p=0.0229；多因素，HR=1.4851，p=0.0385）。USP53高表达患者的预后较低表达患者更差。在功能上，敲低USP53可在体外有效抑制LN229和A172细胞的增殖并诱导凋亡，并在体内减弱LN229细胞的致瘤性。相反，强制表达USP53具有致癌作用。在机制上，USP53靶向ALKB同源物5（ALKBH5）进行去泛素化，从而稳定该蛋白并延长其半衰期。恢复ALKBH5表达可挽救USP53沉默的LN229细胞的增殖缺陷。端粒酶催化亚基端粒酶逆转录酶（TERT）被确定为USP53/ALKBH5轴的下游效应因子，其中ALKBH5通过擦除TERT mRNA上1989 bp位置的m6A修饰来上调TERT RNA表达。总之，这些观察结果表明，USP53/ALKBH5轴通过靶向TERT驱动GBM进展，提示USP53/ALKBH5轴可能作为GBM的潜在治疗靶点。
Abstract
Glioblastoma (GBM) is the most common malignant glioma, with a high recurrence rate and a poor prognosis. Deubiquitinating enzyme ubiquitin-specific peptidase 53 (USP53), known to enhance the stability of downstream proteins, exhibits distinct functions in different tumors. The function of USP53 in GBM progression remains unclear. Analysis of GSE104267 and GSE4290 datasets revealed significant USP53 upregulation in GBM tissues, a finding confirmed by TCGA data comparing GBM (n = 163) with normal brain tissues (n = 207). In univariate and multivariate cox regression analysis, USP53 was identified as an independent risk factor (univariate, hazard ratio (HR) =1.5357, p = 0.0229; multivariate, HR =1.4851, p = 0.0385) for GBM progression. Patients with high expression of USP53 had worse prognosis compared to those with low expression of USP53. Functionally, USP53 knockdown potently inhibited proliferation and induced apoptosis in LN229 and A172 cells in vitro and attenuated tumorigenicity of LN229 cells in vivo. Conversely, forced expression of USP53 had a carcinogenic effect. Mechanistically, USP53 targeted ALKB homolog 5 (ALKBH5) for deubiquitination, thereby stabilizing the protein and prolonging its half-life. Restoring ALKBH5 expression rescued the proliferative deficit in USP53-silenced LN229 cells. Telomerase catalytic subunit telomerase reverse transcriptase (TERT) was identified as a downstream effector of the USP53/ALKBH5 axis, where ALKBH5 upregulated TERT RNA expression by erasing m6A modifications at position 1989 bp on TERT mRNA. Collectively, those observations demonstrate that USP53/ALKBH5 axis drives GBM progression by targeting TERT, indicating that USP53/ALKBH5 axis may serve as a potential therapeutic target for GBM.
如何引用
AMA
Guihong Li, Ting Lei, Erpeng Liu, Jing Shen, Dun Liu, Xuqiang Zhu. USP53-ALKBH5 axis inhibition boosts m6A-modified TERT RNA degradation: A potential therapeutic strategy for glioblastoma.. Biochimica et biophysica acta. Molecular basis of disease. 2027; doi:10.1016/j.bbadis.2026.168419.
APA
Guihong Li, Ting Lei, Erpeng Liu, Jing Shen, Dun Liu, Xuqiang Zhu (2027). USP53-ALKBH5 axis inhibition boosts m6A-modified TERT RNA degradation: A potential therapeutic strategy for glioblastoma.. Biochimica et biophysica acta. Molecular basis of disease. https://doi.org/10.1016/j.bbadis.2026.168419
GB/T 7714
Guihong Li, Ting Lei, Erpeng Liu, Jing Shen, Dun Liu, Xuqiang Zhu. USP53-ALKBH5 axis inhibition boosts m6A-modified TERT RNA degradation: A potential therapeutic strategy for glioblastoma.[J]. Biochimica et biophysica acta. Molecular basis of disease, 2027 doi:10.1016/j.bbadis.2026.168419.
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