METTL1 KO tRNA fragments. METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis and translational control in prostate cancer

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of cancer. Here we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours and increased expression correlates with poor prognosis. 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 tRNAs leading to an accumulation of 5′ tRNA-derived small RNA fragments. 5′ tRNA 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 microenvironment crosstalk and unveil METTL1 inhibition as a promising anti-cancer therapeutic strategy.

日益增多的新兴证据表明，表观转录组修饰（epitranscriptomic marks）在癌症发生发展过程中扮演着至关重要的角色。本研究证实，转运RNA（transfer RNA, tRNA）N7-甲基鸟苷（N7-methylguanosine, m7G）转移酶METTL1在原发性与进展期前列腺肿瘤中均呈高表达，且其表达上调与患者不良预后显著相关。敲低METTL1可显著抑制前列腺癌细胞的增殖能力，并在体内模型中阻断肿瘤进展。与之相对，过表达野生型METTL1可增强细胞增殖，而过表达催化失活型METTL1则无此效应。由此可见，METTL1介导的甲基化修饰在前列腺肿瘤发生中发挥着关键作用。从分子机制层面分析，METTL1敲低会导致tRNA的m7G甲基化修饰缺失，同时促进tRNA的核酸内切酶切割，进而引发5'端tRNA衍生小RNA片段（5' tRNA-derived small RNA fragments）的积累。此类5'端tRNA片段可通过调控翻译程序，优先促进肿瘤生长抑制因子与免疫排斥相关关键调控因子的合成。综上，本研究揭示了tRNA的m7G甲基化修饰在指导癌细胞翻译调控中的核心功能，其对肿瘤生长及肿瘤微环境串扰具有重要意义，并证实METTL1抑制有望成为极具潜力的抗癌治疗策略。