文章目录

靶向PUS7抑制tRNA假尿嘧啶化和胶质母细胞瘤的发生

原文发布日期：2021-08-16

英文摘要：

摘要翻译：

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文章：

靶向PUS7抑制tRNA假尿嘧啶化和胶质母细胞瘤的发生

Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis

原文发布日期：2021-08-16

英文摘要：

Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here, we show that pseudouridine synthase 7 (PUS7) is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in patients with glioblastoma. PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identify PUS7 targets in GSCs through small RNA pseudouridine sequencing and show that pseudouridylation of PUS7-regulated transfer RNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identify chemical inhibitors for PUS7 and show that these compounds prevent PUS7-mediated pseudouridine modification, suppress tumorigenesis and extend the life span of tumor-bearing mice. Overall, we identify an epitranscriptomic regulatory mechanism in glioblastoma and provide preclinical evidence of a potential therapeutic strategy for glioblastoma.

摘要翻译：

伪尿苷是最重要的转录水平修饰（epitranscriptomic），然而其在细胞中的功能尚未完全了解。这里我们发现，在灰质灰质瘤中PUS7合成酶的表达显著高于正常脑组织，且PUS7高度表达与灰质灰质瘤患者预后较差相关联。PUS7的表达和催化活性对原代间充质干细胞（GSC）肿瘤发生至关重要。机制上，我们通过小RNA伪尿苷测序发现，在GSC中PUS7靶标作用，并证明了PUS7调节的转录因子伪尿苷化是关键调控原代间充质 stem细胞的关键调控元件。此外，我们发现可以抑制PUS7发挥作用，这些化合物阻止PUS7介导的伪尿苷修饰，抑制肿瘤发生并延长含有肿瘤的小鼠寿命。总体而言，识别了伪尿苷在灰质灰质瘤中的转录水平调节机制，并为灰质灰质瘤潜在治疗策略提供了临床预实验证据。