Journal Article

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

Carracedo, Arkaitz, Morón-Calvente, Virginia, Elortza, Félix, García-Vílchez, Raquel, Dietmann, Sabine, Ugalde-Olano, Aitziber, Blanco, Sandra, Nombela, Paz, Pandolfi, Pier Paolo, García-Longarte, Saioa, Loizaga-Iriarte, Ana, Marchand, Virginie, Unda, Miguel, Motorin, Yuri, Miguel-López, Borja, Añazco-Guenkova, Ana M., D’Ambrosi, Silvia, Bárcena, Laura, Helm, Mark, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Guil, Sònia, Gonzalez-Lopez, Monika, Zamacola, Kepa, Astobiza, Ianire, Azkargorta, Mikel, Lacasa-Viscasillas, Isabel, Di Domenico, Tomás, Aransay, Ana M., De Las Rivas, Javier, Zabala-Letona, Amaia, Paniagua, Alejandro, Fernández, Sonia, López, Judith, Sánchez-Martín, Manuel A., Mendizabal, Isabel

2023

Overview

Newly 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 N 7 -methylguanosine (m 7 G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m 7 G 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 m 7 G tRNA methylation in cancer cell translation control and tumour biology.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 7-methylguanosine / Analysis / Androgens / Biological response modifiers / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Biotechnology industry / Cancer Research / Carcinogenesis - genetics / Cell Transformation, Neoplastic / Datasets / Development and progression / Diagnostic reagents industry / Epitranscriptome / Humans / Hyperplasia / Immunotherapy / Inflammation / Interferon / Life Sciences / Male / Medical prognosis / Metastases / Metastasis / Methylation / Methylene blue / Methyltransferases - genetics / Oncology / Prostate cancer / Prostatic Neoplasms - genetics / Protein expression / Proteins / RNA modifications / RNA Processing, Post-Transcriptional / Scientific equipment and supplies industry / Transcription, Genetic / Transfer RNA / Translation / tRNA / tRNA fragments / Tumorigenesis / Tumors / Tumour microenvironment (TME)