N1-methyladenosine\xa0methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism

Yanying Wang,Xiaoyu Li,Chengqi Yi,Yang Gu,Ziheng Zhou,Zusen Fan,Xushen Xiong,Lei He,Dan Dominissini,Jianyi Wang,Yong Tian,Jing Wang,Xiaoxiao Zhu

doi:10.1038/s41467-021-26718-6

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.

Highlights

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
We reveal that m1A methylation signals are significantly increased in higher grade HCC, especially in patients with microvascular invasion (MVI). m1A signals in RNA are hypermethylated in liver cancer stem cells (CSCs)
HCC accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity

Summary

Introduction

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. M1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. 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. The underlying mechanism remains elusive in liver cancer and liver CSCs. Here, we reveal that m1A methylation signals are significantly increased in higher grade HCC, especially in patients with microvascular invasion (MVI). M1A signals in RNA are hypermethylated in liver CSCs. TRMT6/TRMT61A mediated m1A methylation participates in liver tumourigenesis through promotion of PPARδ protein translation, leading to cholesterol biogenesis for activation of Hh signaling

Methods

Findings

Conclusion