N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism.
N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism.
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tRNA 中的 N1-甲基腺苷甲基化通过调节胆固醇代谢驱动肝脏肿瘤发生
DOI：
10.1038/s41467-021-26718-6
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发表时间：
2021-11-02
影响因子：
16.6
通讯作者：
Fan Z
中科院分区：
文献类型：
--
作者：
Wang Y;Wang J;Li X;Xiong X;Wang J;Zhou Z;Zhu X;Gu Y;Dominissini D;He L;Tian Y;Yi C;Fan Z
肝细胞癌（HCC）占原发性肝癌的大多数，具有高复发性和异质性的特点，但其机制尚不清楚。在这里，我们发现肝细胞癌 (HCC) 患者肿瘤组织中 tRNA 中的 N1-甲基腺苷甲基化 (m1A) 显着升高。此外，m1A 甲基化信号在肝癌干细胞 (CSC) 中增加，并且与 HCC 患者的生存呈负相关。 TRMT6 和 TRMT61A 形成 m1A 甲基转移酶复合物，在晚期 HCC 肿瘤中高表达，与 HCC 生存呈负相关。 TRMT6/TRMT61A 介导的 m1A 甲基化是肝脏肿瘤发生所必需的。从机制上讲，TRMT6/TRMT61A 升高 tRNA 子集中的 m1A 甲基化，以增加 PPARδ 翻译，进而触发胆固醇合成，激活 Hedgehog 信号传导，最终驱动肝脏 CSC 的自我更新和肿瘤发生。最后，我们确定了一种有效的 TRMT6/TRMT61A 复合物抑制剂，对肝癌发挥有效的治疗作用。据报道，代谢适应会促进癌症，但其潜在机制尚不清楚。在此，作者表明，tRNA 中的 m1A 甲基化可调节肝癌干细胞中的胆固醇代谢，并且 m1A 抑制可减少肝细胞癌临床前模型中的肿瘤发生。
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer. Metabolic adaptation has been reported to promote cancer, yet the underlying mechanisms are not clear. Here, the authors show that m1A methylation in tRNA regulates cholesterol metabolism in liver cancer stem cells and m1A inhibition decreases tumourigenesis in preclinical models of hepatocellular carcinoma.