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

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.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC8563902 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature