METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of cancer; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5’tRNA fragments. 5′ tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy, leading to decreased tumour progression. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translational control and tumour biology. Sequences of RNAs bound to METTL1 in prostate cancer cell lines PC3. Photoactivatable-ribonucleoside-enhanced cross-linking immunoprecipitation (PAR-CLIP) was applied to PC3 cells expressing HA-METTL1.Empty vector was used as control. METTL1 was IP using anti-HA antibodies. RNAs bound to METTL1 were extracted and sequenced.