N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism

Yanying Wang (), Jing Wang, Xiaoyu Li, Xushen Xiong, Jianyi Wang, Ziheng Zhou, Xiaoxiao Zhu, Yang Gu, Dan Dominissini, Lei He, Yong Tian (), Chengqi Yi () and Zusen Fan ()
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Yanying Wang: Chinese Academy of Sciences
Jing Wang: Chinese Academy of Sciences
Xiaoyu Li: Peking University
Xushen Xiong: Peking University
Jianyi Wang: Chinese Academy of Sciences
Ziheng Zhou: Chinese Academy of Sciences
Xiaoxiao Zhu: Chinese Academy of Sciences
Yang Gu: Chinese Academy of Sciences
Dan Dominissini: Tel Aviv University
Lei He: PLA General Hospital
Yong Tian: Chinese Academy of Sciences
Chengqi Yi: Peking University
Zusen Fan: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26718-6

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