Author:
García-Vílchez Raquel,Añazco-Guenkova Ana M.,Dietmann Sabine,López Judith,Morón-Calvente Virginia,D’Ambrosi Silvia,Nombela Paz,Zamacola Kepa,Mendizabal Isabel,García-Longarte Saioa,Zabala-Letona Amaia,Astobiza Ianire,Fernández Sonia,Paniagua Alejandro,Miguel-López Borja,Marchand Virginie,Alonso-López Diego,Merkel Angelika,García-Tuñón Ignacio,Ugalde-Olano Aitziber,Loizaga-Iriarte Ana,Lacasa-Viscasillas Isabel,Unda Miguel,Azkargorta Mikel,Elortza Félix,Bárcena Laura,Gonzalez-Lopez Monika,Aransay Ana M.,Di Domenico Tomás,Sánchez-Martín Manuel A.,De Las Rivas Javier,Guil Sònia,Motorin Yuri,Helm Mark,Pandolfi Pier Paolo,Carracedo Arkaitz,Blanco Sandra
Abstract
AbstractNewly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; 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. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology.
Funder
Consejo Superior de Investigaciones Cientificas
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine