文章目录

苏氨酸通过yrdc介导的密码子偏倚翻译重编程为胶质母细胞瘤提供燃料

原文发布日期：2024-03-22

英文摘要：

摘要翻译：

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文章：

苏氨酸通过yrdc介导的密码子偏倚翻译重编程为胶质母细胞瘤提供燃料

Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming

原文发布日期：2024-03-22

英文摘要：

Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t6A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t6A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t6A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment.

摘要翻译：

癌症通常会重新编程翻译和代谢，但很少了解癌干细胞中这两个特征是如何协调工作的。我们发现胶质母细胞样癌细胞（GSCs）表现出升高的蛋白质翻译活动。为了揭示其背后机制，我们进行了CRISPR筛选，并在GSCs中鉴定出YRDC为最重要的转录因子RNA（tRNA）修饰酶之一。YRDC催化ANN解码tRNA物种上形成N6-丝氨酸酰胺乙酰腺苷酸（t6A）。靶向抑制YRDC降低了t6A的生成，减少了全局翻译并抑制了肿瘤生长（体外和体内）。丝氨酸是YRDC的关键底物。GSCs中积累的丝氨酸通过YRDC促进了t6A的形成，并将蛋白质代谢重编程为与ANN密码子偏差相关的分裂相关基因表达。饮食限制给定的丝氨酸（TR）降低了肿瘤中的t6A生成，减缓了异物瘤生长并提高了化疗和抗分裂治疗的抗肿瘤疗效，为癌症治疗提供了一种分子干预的可能性。