Liver cancer

Hepatocellular carcinoma

Methylation

Bioinformatics

Biology

Gene

Cancer

Gene expression

DNA methylation

Signal transduction

Hedgehog signaling pathway

Cell biology

Cancer research

Genetics

Methyltransferase

Nature Communications

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 N 1 -methyladenosine methylation (m 1 A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m 1 A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m 1 A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m 1 A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m 1 A 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.

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