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TRMT6介导的tRNA m1A修饰作为组蛋白合成的翻译检查点并促进结直肠癌进展

TRMT6-mediated tRNA m1A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression

原文发布日期: 2025-06-03

英文摘要:

摘要翻译：

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TRMT6介导的tRNA m1A修饰作为组蛋白合成的翻译检查点并促进结直肠癌进展

TRMT6-mediated tRNA m1A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression

原文发布日期: 2025-06-03

英文摘要:

Transfer RNA modifications have emerged as critical regulators of translational reprogramming, yet their roles in colorectal cancer (CRC) remain largely elusive. Here, we find that tRNA N1-methyladenosine (m1A) methyltransferase TRMT6 is upregulated in human CRC tissues and high TRMT6 expression correlates with poor survival in patients with CRC. Using orthotopic, metastatic and conditional knockout mouse models, we establish the oncogenic role of TRMT6 in CRC. Mechanistically, TRMT6 increases tRNA m1A levels by maintaining the stability of the TRMT6–TRMT61A complex. Targeting TRMT6-mediated tRNA m1A modification in CRC cells destabilizes tRNA-Lys-TTT-1-1 and impairs histone mRNA translation in a codon-biased manner, thereby restricting histone synthesis and hindering cell cycle progression. Our study provides evidence that TRMT6 functions as a translational checkpoint in the accelerated histone synthesis of CRC cells, highlighting TRMT6 as a promising target for potential anti-CRC therapies.

摘要翻译：

转运RNA修饰已成为翻译重编程的关键调控因子，但其在结直肠癌（CRC）中的作用机制尚不明确。本研究发现，tRNA N1-甲基腺苷（m1A）甲基转移酶TRMT6在人类CRC组织中表达上调，且高TRMT6表达与患者不良预后显著相关。通过原位移植、转移性及条件性基因敲除小鼠模型，我们证实了TRMT6在CRC中的致癌作用。机制上，TRMT6通过维持TRMT6-TRMT61A复合物稳定性来提升tRNA m1A修饰水平。靶向抑制CRC细胞中TRMT6介导的tRNA m1A修饰后，tRNA-Lys-TTT-1-1稳定性降低，并以密码子偏好性方式损害组蛋白mRNA翻译，从而限制组蛋白合成并阻滞细胞周期进程。本研究首次揭示TRMT6通过充当CRC细胞加速组蛋白合成的翻译检查点发挥作用，为抗CRC治疗提供了潜在新靶点。