Guanosine-7 tRNA methylation steers tRNA-derived fragment biogenesis and translational control in prostate cancer

ABSTRACT: Abstract Transfer RNAs (tRNAs) are exceptionally subject to modifications, including methylation. While mRNA methylation is emerging as an important regulator of biological and pathological processes in cancer, how post-transcriptional methylation of tRNAs contributes to cancer is largely unknown. Here we show that the RNA N7-methylguanosine (m7G) methyltransferase METTL1 is highly differentially expressed in prostate cancer compared to non-tumour prostate tissues. METTL1 expression regulation is mediated by the oncogenic regulator PI3K, which is altered in most advanced prostate tumours. Knockdown of METTL1 dramatically inhibits prostate cancer cell growth and tumour progression in vivo. In contrast, overexpression of the wild type but not the catalytically inactive METTL1 potentiates cell growth. Thus, METTL1-mediated methylation is important for prostate tumorigenesis. Mechanistically we find that METTL1 depletion causes loss of m7G tRNA methylation and increases endonucleolytic cleavage of Cysteine tRNA leading to an accumulation of 5′ tRNA-derived small RNA fragments. 5′ tRNA-derived fragments steer translation control to favour synthesis of key regulators of tumour growth suppression and immune rejection. In summary, our findings uncover a critical function of m7G tRNA methylation in directing translation control in cancer cells with important implications for tumour growth and unveil METTL1 inhibition as a promising anti-cancer therapeutic strategy. induction and maintenance of naïve human pluripotency are governed by distinct signaling requirements. tRNAs from WT and METTL1 KO cells were subjected to NaBH4-Aniline treatment followed by RNA-seq to unveil methylation of guanosine-7 in tRNA with nucleotie resolution. RNA-seq libraries were also analysed to unveil tRNA stability or processing into tRNA-derived fragments in METTL1 KO cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190911 | GEO | 2023/08/08

REPOSITORIES: GEO